Cutaneous findings

Café-au-lait macules (CALM) are light to dark brown sharply defined oval macules and patches which can occur on almost any skin surface (Fig. 29.2A). Infants with ≥6 café-au-lait macules >5 mm in diameter that are not confined to a single segmental region, should be evaluated and managed as though they have NF-1, even without other signs of NF-1, because of the high likelihood that they will develop other diagnostic signs with time. At puberty, if other features are lacking, the approach and diagnosis can be reconsidered.

Intertriginous freckling of the axillary and inguinal regions may occasionally be present in infancy, but most often present between 2–10 years of age (Fig. 29.2B). Although freckling on the neck and trunk is common in NF-1, it is not accepted as a diagnostic criterion.

Peripheral neurofibromas are infrequent in early childhood NF-1, occurring in only 14% of children less than 10 years of age.⁶ Often the first sign of dermal neurofibromas are 3–6 mm, light blue, minimally raised papules which are most easily detected with side lighting. It has been suggested that a subset of children with large deletions of the NF-1 gene typically present with multiple neurofibromas in early childhood.⁷

Plexiform neurofibromas may be apparent at birth or soon thereafter; however because they are often internal, may be difficult to detect. They occur in at least 25% of affected individuals (Fig. 29.2C). Most have overlying hyperpigmentation; some – but not all – have increased vascularity resembling a vascular anomaly or hypertrichosis resembling a congenital melanocytic nevus. Plexiform neurofibromas may grow rapidly and interdigitate with and surround normal structures. Radiologic imaging and neurosurgical consultation should be considered if lesions are extensive or close to major nerve bundles.

Extracutaneous findings

Optic gliomas are astrocytomas arising anywhere along the optic pathway. These lesions tend to arise in infancy or early childhood. Half of the tumors are symptomatic, causing loss of visual acuity, decreased field of vision, proptosis, or interference with the hypothalamopituitary axis. Symptomatic optic gliomas are often diagnosed by 6 years of age.

Lisch nodules are pigmented iris hamartomas that rarely present in infants, and only 20% of individuals under 5 years of age with NF-1 have Lisch nodules. They are best seen on slit-lamp examination and do not result in functional disability. Congenital glaucoma occurs in less than 0.05% of individuals with NF-1 and may present with an ipsilateral neurofibroma of the eyelid.

Relatively short stature and large head size are frequent findings and more common than the more diagnostic skeletal changes, pseudoarthrosis and sphenoid wing dysplasia. Pseudoarthrosis represents the failure of union after fracture. It is always unilateral and most commonly presents in the tibia as anterolateral bowing. Ultimately, pseudoarthrosis can progress to severe deformity. Sphenoid wing dysplasia is a unilateral defect of the orbit present in approximately 5% of individuals with NF-1 and results in a change in orbit structure. Approximately half of those cases with sphenoid wing dysplasia develop an ipsilateral temporal–orbital plexiform neurofibroma, and half of individuals presenting with a temporal–orbital tumor also have an underlying plexiform neurofibroma. Learning disabilities occur in approximately 50% of children with NF-1. The main learning difficulties include reading, deficits in perceptual skills (visuospatial) and executive functioning. Attention issues are also common.⁸

Etiology and pathogenesis

NF-1 is due to an autosomal dominant mutation localized to chromosome 17 that results in defects in neurofibromin, a tumor suppressor protein that stimulates hydrolysis of guanosine triphosphate (GTP) bound to ras.⁹

Differential diagnosis and diagnosis

Café-au-lait macules may be found in many other conditions, including segmental pigmentary disorder and McCune–Albright syndrome (see Chapter 24). Additional differential diagnoses for multiple café-au-lait macules are shown in Box 29.2. Genetic testing for NF-1 is available from several commercial and research laboratories (see: www.genetests.org, for specific information). Decisions regarding whether laboratory-based NF testing is appropriate are best made in conjunction with a geneticist and genetic counselor.

Treatment and care

Patients with neurofibromatosis require age-related anticipatory guidance counseling and regular follow-up with a pediatrician, ophthalmologist and geneticist. Additional specialists can be included, based on symptoms or complications and may include orthopedics, neurology, dermatology, neuropsychology, and neurosurgery (Box 29.3). Ophthalmologists and neurologists should evaluate for optic nerve pathway tumors and glaucoma. Anterolateral tibial bowing when present require prompt orthopedic evaluation, because the critical time for fracture and poor healing is infancy to early childhood.⁶ Periodic evaluation for scoliosis is also necessary. Regular physical examinations should include careful measurement of blood pressure because of a higher incidence of hypertension secondary to renovascular disease, vasoactive secreting tumors, and coarctation of the aorta.⁶ Head circumference should be monitored because of the risk of hydrocephalus and the occurrence of macrocephaly without hydrocephalus. Careful developmental assessment is a key part of management, as the risk of neurologic abnormalities and learning disabilities is increased.

Dermal neurofibromas are benign and should only be excised if they are symptomatic or disfiguring. Plexiform neurofibromas require close evaluation. Skin should be palpated carefully as plexiform neurofibromas may remain below the surface. If there are symptoms or neurologic abnormalities on clinical exam, MRI scans should be obtained to determine the extent of plexiform neurofibromas. Serial imaging or volumetric MRI may be necessary to assess potential growth. Pain and/or growth may herald malignant transformation, but this is exceedingly rare in infancy. Neurologic compromise may result from perineural extension, however, and neurology and/or neurosurgery may need to be consulted for plexiform lesions near neurovascular structures (such as the neck, axilla and spinal area).⁶ Orbitotemporal neurofibromas may be better managed by numerous surgical procedures over time; plastic surgery should be involved early for management of these tumors.

Cutaneous findings

The neonate with Noonan syndrome is unlikely to have skin manifestations other than nuchal webbing and peripheral lymphedema that suggest the diagnosis. Keratosis pilaris atrophicans faciei (ulerythema ophryogenes), characterized by horny, whitish, hemispherical, or acuminate papules at the opening of pilosebaceous follicles, is generally noted in older children, but may manifest in the external third of the eyebrows by a few months after birth. Some children with Noonan syndrome have multiple CALM and/or lentigines.

Extracutaneous findings

Neonates have a characteristic facial appearance consisting of a tall forehead, low posterior hairline, hypertelorism, down­slanting palpebral fissures, epicanthal folds, short and broad, depressed nasal root, deeply grooved philtrum and microg­nathia. The chest shape is unique with superior pectus carinatum and inferior pectus excavatum. Feeding difficulties, gastroesophageal reflux and failure to thrive are frequent problems in infancy. Unilateral or bilateral cryptorchidism are common in boys. Infants are at risk for transient monocytosis, thrombocytopenia and myeloproliferative disorder.¹² Coagulation defects occur in approximately one-third of patients with Noonan syndrome and may present with easy bruising or prolonged bleeding times. There is a slightly increased risk of hematologic malignancy (most commonly juvenile myelomonocytic leukemia, JMML) compared with the general population. The classic congenital heart defect in Noonan syndrome is pulmonic stenosis.

Etiology and pathogenesis

The incidence of Noonan syndrome is approximately 1 in 1000–2500 live births.¹³ Noonan syndrome may be caused by a mutation in one of several genes in the RAS-MAPK signaling pathway, including PTPN11, SOS1, KRAS, NRAS, RAF1, SHOC2, CBL, and BRAF.¹⁴ PTPN11 and CBL mutations have a higher rate of bleeding diathesis and JMML. Patients with SOS1 mutations have a lower rate of intellectual disability. SHOC2 mutations have been associated with a Noonan phenotype with loose anagen hair.¹⁵ PTPN11 mutations are also the genetic basis of Noonan with multiple lentigines (formerly known as LEOPARD syndrome;¹⁶ see Chapter 24).

Differential diagnosis

In the neonatal period, the RASopathies can be very difficult to distinguish as they share the features of congenital heart defects, severe feeding difficulties and developmental delay.¹⁷ Later in infancy, facial and ectodermal features become more distinct for each of the RASopathies. Cardiofaciocutaneous syndrome and Costello syndrome are described in more detail below.

Treatment and care

Patients with Noonan syndrome should be monitored for growth deficiency and developmental delay. Electrocardiogram and echocardiography should be performed at the time of diagnosis and repeated as indicated based on findings. A renal ultrasound is recommended at diagnosis. Coagulopathy work-up should be performed if the patient has a history of either easy bruising or prolonged bleeding.¹⁴

Cutaneous findings

There is a very high prevalence of cutaneous findings in TSC.³⁷ Hypomelanotic macules are usually present at birth or appear within the first few months of life and ultimately are present in approximately 90% of TSC patients. Classically, they present as an ‘ash leaf macule,’ an oval area with reduction in pigment (Fig. 29.8A). These areas can also be irregular in outline and shape, or very small and guttate (confetti-like) (Fig. 29.8B). In fair-skinned infants, a Wood’s lamp examination may be necessary for detection. They can also occur on the scalp, with lightening of the hair within the patch. A single, hypopigmented macule in an infant, without other features of TSC, should not cause concern,³⁸ but multiple lesions (≥3) should lead to further investigation.

Classic facial angiofibromas typically appear after 4 years of age, however fibrous plaques resembling coalescence of angiofibromas may be present over the scalp, face, or neck at birth or appear shortly thereafter, as firm slightly raised patches or plaques that are commonly erythematous (Fig. 29.8C). Shagreen patches – firm, palpable thickened dermal plaques – can occur in the lumbar region as a roughened area of erythematous skin with a rubbery consistency or develop in other areas of the torso (Fig. 29.8D). They range in size from a few millimeters to 15 cm in diameter, and generally appear by adolescence but are infrequent in young infants. Periungual fibromas are similarly uncommon in the first decade. Gingival fibromas are a less common feature, but occasionally develop in young children (Fig. 29.8E).

Etiology and pathogenesis

TSC may be caused by an autosomal dominant mutation in the TSC1 gene (encoding hamartin) or the TSC2 gene (encoding tuberin). The two proteins form a complex that is involved with the phosphoinositide-3-kinase (PI3K) signaling pathway, which regulates cell growth and proliferation (Fig. 29.6).⁴⁴

Differential diagnosis

The differential diagnosis for the hypopigmented macules seen in the neonatal period includes vitiligo, nevus depigmentosus, nevus anemicus, and piebaldism. A single lesion, or several lesions occurring along the lines of Blaschko suggests the diagnosis of nevoid hypopigmentation rather than TSC (see Chapter 23). Connective tissue nevi may be sporadic and have also been associated with Buschke–Ollendorff or Proteus syndrome. Angiofibromas have been described in MEN1⁴⁵ and Birt–Hogg–Dubé syndrome, and also as an isolated autosomal dominant disorder.

Treatment and care

Consensus recommendations for screening and evaluation of TSC were proposed in 1998 and updated in 2000 (Box 29.6).^43,46 The Scottish Clinical Genetics Service and the UK Tuberous Sclerosis Association have also created clinical guidelines. Neurology and/or neurosurgery should be consulted for management of seizures, brain tumors, and shunting of obstructive hydrocephalus. Ophthalmology should also examine patients to assist in confirming the diagnosis. Renal ultrasound or renal MRI are important to screen angiomyolipomas. This may also help to identify patients with coexisting polycystic kidney disease due to a contiguous gene deletion syndrome involving the TSC2 and PKD1 genes. Echocardiography and electrocardiogram are recommended at diagnosis for confirmation (to detect cardiac rhabdomyomas and arrhythmias) and to screen for aortic aneurysms.⁴⁷

Pulsed dye laser has been recommended for flat erythematous angiofibromas, and both Potassium titanyl phosphate (KTP) laser and carbon dioxide laser are used to treat more elevated lesions, but are rarely indicated in infants.⁴⁸ Fibrous forehead plaques are generally left untreated, but may also be treated with lasers or surgery. Several case reports have recently described the utility of topical rapamycin for the treatment of angiofibromas. This approach holds promise, but further study is needed to establish the safety, efficacy and dosing guidelines.^49,50

Cutaneous findings

Almost all individuals with Proteus syndrome have a dermatologic manifestation. Over 40% of affected neonates will demonstrate at least some evidence of the disease at birth, such as epidermal nevi or vascular malformations.⁵² The three main cutaneous findings are epidermal nevi, vascular malformations, and soft subcutaneous masses. Epidermal nevi are usually linear and verrucous, but may be macular and hyper- or hypopigmented. Malformations may be venous, capillary, and/or lymphatic.⁵³ The cerebriform connective tissue nevus, when on the sole of the foot, is caused by hyperplasia of cutaneous and subcutaneous tissues and considered virtually pathognomonic.⁵⁴ The tissue is very firm; similar lesions may also occur on the hands, perinasal area, or near the canthus. Prominent cutaneous venous structures may occur as a result of patchy dermal hypoplasia. Macrodactyly and adipose overgrowth may also be observed.

Extracutaneous findings

Overgrowth in Proteus syndrome is disproportionate, asymmetric, progressive, distorting, and persistent (see Fig. 29.7). Overgrowth usually presents between 6 and 18 months of age and can occur in areas that were completely normal at birth. Overgrowth affects most tissues including bones, cartilage, muscle, and connective tissues. At least some overgrowth and asymmetry is present at birth in 17.5% of cases.⁵² Orifices may be affected, causing respiratory obstruction, conductive hearing loss, or gastric outlet obstruction. Cystic degeneration of the lungs may lead to pneumonia.⁵⁵ Affected individuals are predisposed to deadly deep venous thrombosis and pulmonary embolism.⁵⁶ The central nervous system is commonly affected by hemimegalencephaly (unilateral enlargement of the brain), but most patients are asymptomatic.⁵⁷ Eye complications are common and range from strabismus to epibulbar hamartomas. Ovarian cystadenomas and cystic lesions of the epididymis are also common.

Etiology and pathogenesis

The cause of Proteus syndrome is a de novo post-zygotic activating mutation in the AKT1 oncogene. Proteus features are an example of somatic mosaicism that is lethal in the non-mosaic state.⁵¹ Because Proteus is a mosaic disorder, biopsy of affected tissue is required to make a genetic diagnosis.

Differential diagnosis

Proteus syndrome has been overdiagnosed,⁵⁸ prompting the creation of diagnostic criteria (Box 29.7) to separate Proteus syndrome from other overgrowth syndromes, many of which share asymmetric hypertrophy as a feature but almost always to a less severe degree.⁵² Proteus stands apart by having fairly rapid postnatal progression, relentless deforming overgrowth and a poor prognosis.⁵⁸

Differential diagnosis of Proteus and similar disorders

Maffucci syndrome consists of multiple enchondromatosis (which may be confused with hyperostosis) and vascular malformations.⁶⁷ Klippel–Trenaunay (MIM #149000) syndrome consists of vascular malformations with overgrowth, typically in the same segment. Axillary freckling and neurofibromas help distinguish neurofibromatosis.

Management

Management of these syndromes depends on the specific disease; if overgrowth is severe – as in Proteus syndrome – management is often very difficult. A multidisciplinary approach best addresses all aspects of the disease adequately. Ongoing ophthalmology, neurology, and developmental assessment exams are recommended.⁵² Caregivers should be informed of the risk of pulmonary embolism and stroke so that healthcare providers consider it if an emergency arises.⁵² Orthopedic surgery should be consulted before functional deficits appear and before the patient becomes too debilitated to undergo surgery. Cancer surveillance is an important part of management as dictated by clinical symptoms; routine imaging is not recommended.⁶⁸

Isolated hemihyperplasia places individuals at increased risk (5.9%) for embryonal malignancies such as Wilms tumor, adrenal cell carcinoma and hepatoblastoma.²⁸ A study of 260 children with hemihyperplasia⁶⁹ reported that the risk in truly isolated idiopathic hemihyperplasia is lower (1.2%) and in syndrome-related hemihyperplasia higher (10%) than previously reported. The risk of malignancy in specific syndromes with hemihyperplasia, including HH-ML and excluding Klippel–Trenaunay, is not clear. Until further information becomes available, screening with abdominal ultrasound every 3–6 months until age 8, checking of blood alpha fetoprotein level every 3 months until age 4 and referral to a geneticist for identifying associated syndromes is recommended.²⁸ Individuals with SOLAMEN syndrome have a risk of malignancies associated with Cowden (PTEN hamartoma) syndrome.

Cutaneous findings

Patients with hypohidrotic ectodermal dysplasia often present at birth with a collodion membrane or marked scaling of the skin, which may be misconstrued as a marker of congenital ichthyosis or of postmaturity.⁷⁶ After membrane shedding, the skin is soft, thin, and light-colored with fine periorbital wrinkling (Fig. 29.10A,B). Even in the neonatal period, the hair tends to be absent or sparse, short, and blond. The nails are usually normal. Patients have an increased frequency of atopic dermatitis, particularly periorbital dermatitis.

In cases without a positive family history, repeated bouts of unexplained fevers most often bring infants with HED to medical attention. As the infants produce little to no sweat, they cannot make the appropriate physiologic response to increased environmental temperature, resulting in core temperature elevation. Diminished or absent sweat pores may be appreciated both clinically and histologically.

Extracutaneous findings

Most infants with HED have a typical facies, easily recognizable to educated family members and/or physicians, characterized by a square forehead with frontal bossing, a flattened nasal bridge with prominent nostrils, wide cheekbones with flat malar ridges, a relatively thick, everted lower lip, prominent chin, and small, pointed, low-lying ears. Lacrimal and mucous glands are hypoplastic, leading to reduced tearing, chronic thick nasal discharge, and impacted cerumen with an increased frequency of otitis media and respiratory tract infections. As the teeth are not present in the neonatal period, the typical peg-shaped or missing teeth cannot be used to aid in diagnosis, but dental X-rays can demonstrate these findings, even in young infants.

Etiology and pathogenesis

Most patients are male and carry the X-linked form; however, mutations in several individual genes with autosomal dominant and recessive inheritance patterns may lead to identical developmental abnormalities of the hair and glands. All of the involved genes are within the ectodysplasin signaling pathway (Fig. 29.11) and include ectodysplasin-A1 (EDA-A1), Eda-A1 receptor (EDAR), and EDAR associated death domain (EDARADD).^77,78 Female carriers of ectodysplasin mutations show varied manifestations including more subtle clinical findings overall, or distinct manifestations such as hypohidrosis following the lines of Blaschko.

Differential diagnosis

Hypohidrosis may be found in another group of ectodermal dysplasias resulting from autosomal dominant mutations in p63 (Rapp–Hodgkin syndrome, AEC syndrome, EEC syndrome, limb–mammary syndrome, or ADULT syndrome), but that group has associated facial clefting and split-hand/foot malformations.^79,80

Treatment and care

Temperature must be carefully regulated with cool baths, air conditioning, light clothing, spray-mist bottles to dampen clothing during activities, and avoidance of warm environments (Box 29.8).⁸¹ Some families find commercially available cooling suits to be helpful. Reduced glandular secretion may be treated with lubricating eye drops and nasal irrigation. Treatment of recurrent otitis media, respiratory infections, atopic dermatitis, and asthma should be individualized. Dental manifestations should be managed early.

Extracutaneous findings

The extracutaneous findings are what help separate this disorder from HED. Patients are prone to severe and sometimes fatal infections. This can include infection with either Gram-positive or Gram-negative bacteria leading to skin and soft tissue abscesses, acute otitis media, pneumonia, osteomyelitis, gastrointestinal infections and sepsis.

Etiology and pathogenesis/management

HED-ID (MIM #300291) is most often inherited in an X-linked manner and is due to mutations in IKBKG (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma).⁸² Autosomal dominant forms also exist and are due to mutations in IκBα. Both mutations result in impaired NF-κB signaling (Fig. 29.11).⁸³ Somatic mosaic mutations in NEMO can also occur which leads to a milder phenotype.^83,84

Defective NF-κB signaling is responsible for both defective ectodermal appendage development as well as the immunodeficiency in these patients. Antibody response is poor, natural killer cells are ineffective and T cells lack development and maturation which accounts for the wide variety of infectious diseases patients with HED-ID encounter.

The ED components are managed similar to those in HED; manifestations of the immunodeficiency require a multidisciplinary approach with immunologists and infectious disease specialists.

Extracutaneous findings

The most characteristic ocular finding is retinal vascular proliferation,⁸⁷ which can result in bleeding, fibrosis, retinal detachment,⁸⁸ and in 10% of patients, enough scarring to produce permanent blindness.⁸⁶ All neonates with IP need prompt and periodic evaluation by an experienced ophthalmologist. The magnitude of risk of central nervous system abnormalities is controversial but probably lower than previously believed, with current estimates varying from 10% to 30%.^85,89 Most neurologic features present in the neonatal period and include seizures, encephalopathy, encephalitis and ischemic stroke.⁹⁰

Etiology and pathogenesis

IP results from mutations in the X chromosomal gene IKBKG (previously known as NEMO, NF-κB essential modulator),⁹¹ which is involved in immune, inflammatory, and apoptotic pathways, as discussed above.⁹¹ The mutation is believed to be lethal in affected 46,XY males, but male cases have been reported in the setting of XXY genotype, and other cases in males are presumably due to somatic mosaicism or half-chromatid mutations.

Differential diagnosis

In the newborn, IP must be differentiated from other causes of blistering, including infections (bacteria and herpes simplex virus), erythema toxicum, and epidermolysis bullosa (see Chapters 10 and 11). The warty phase of IP is unique, but may be confused with a linear epidermal nevus. Linear and whorled nevoid hypermelanosis may appear identical to stage 3 of IP. Although history helps to distinguish between the two conditions, a biopsy may be necessary, as stage 3 IP has occurred as late as 15 months of age without any antecedent skin changes.

Treatment and care

The skin changes of IP do not require any treatment other than wound care for blisters to prevent secondary infection. A baseline eye examination and close follow up by an ophthalmologist and a full neurological assessment with anticipatory evaluation for the possibility of neurologic deficits are appropriate. Dental evaluation should be considered after teeth erupt.

Cutaneous findings

The upper and lower eyelids of the newborn have fine strands of skin between them (so-called ankyloblepharon), which are pieces of tissue that can be thick or thin, may tear spontaneously, or require surgical lysis (Fig. 29.14A). These are a cardinal feature of this condition, but are not mandatory for diagnosis. During the newborn period, the rest of the skin is erythematous and fissured with a collodion membrane appearance, resembling bullous congenital ichthyosiform erythroderma with peeling, erythema, and erosions (Fig. 29.14B) (see also Chapters 10 and 19). After the membrane has shed over the first few weeks, the underlying skin is dry and thin. Recurrent scalp infections, erosions, and granulation tissue may have their onset in early infancy and are present in two-thirds to three-quarters of older infants, children, and adults with this condition.¹⁰¹ The hair is sparse and coarse. Sweating is usually not significantly affected. Nail dystrophy is variable. The nails can be thickened and malformed, thin or absent.

Extracutaneous findings

Cleft palate, with or without cleft lip, is the third major sign of AEC syndrome, occurring in 80% of affected newborns. The reported hypodontia associated with the condition may reflect the degree of severity of the clefting, rather than a primary ectodermal defect.

A few males with AEC have had hypospadias. External ear malformations are described in some patients. Supernumerary nipples and ectopic breast tissue occur in a minority of cases. There may be tear duct abnormalities and recurrent lid inflammation.

Differential diagnosis

Other diagnoses to be considered when presented with an infant with cleft palate and a collodion membrane include EEC (ectodermal dysplasia, ectrodactyly, cleft lip/palate syndrome), distinguished by its limb involvement, and Rapp–Hodgkin syndrome. Not surprisingly, there is considerable overlap between Rapp–Hodgkin and AEC syndromes, as they are allelic. The presence of ankyloblepharon can distinguish between the two, being a key characteristic of AEC, but now that the genetics of the conditions are appreciated, a true distinction may not be absolutely necessary.

Treatment and care

Treatment is limited to surgical management of eyelid involvement and oral facial clefting. The use of light emollients may speed the shedding of dry, cracking neonatal skin. Careful handling of the scalp and prompt attention to secondary bacterial infection may decrease long-term complications. Patients will require ongoing ocular hygiene.

Extracutaneous findings

Ectrodactyly (abnormal development of the median rays of the hands and feet) serves to distinguish this disorder from other ectodermal dysplasias and occurs in 80–100% of affected individuals. Depending on the series, cleft palate with or without cleft lip occurs in 70–100% of patients.^102,103 Lacrimal duct hypoplasia or atresia is seen in over 90% of affected individuals, leading to excessive tearing, conjunctivitis, and blepharitis.^104–106 Genitourinary malformations affect over one-third of patients. Chronic otitis media with secondary hearing loss occurs in 50%.¹⁰⁷

Etiology and pathogenesis

Three forms of EEC have been described, EEC1 (MIM #129900), EEC2 (MIM #602077), and EEC3 (MIM #604292). Most individuals harbor mutations in p63, a tumor-suppressor gene (see above).¹⁰⁸

Differential diagnosis

The diagnosis of EEC is self-evident when all three features (ectrodactyly, ectodermal dysplasia and clefting) are present. In the absence of limb defects, other ectodermal dysplasias asso­ciated with oral facial clefting, including Hay–Wells, Rapp–Hodgkin, and limb–mammary syndromes, need to be considered. Other diseases with limb defects include odontotrichomelic syndrome, which presents with severe absence deformities of the limbs, and Adams–Oliver syndrome (aplasia cutis congenita with limb defects), which has neither clefting nor ectodermal defects other than localized absence of skin.

Treatment and care

Treatment is mainly surgical. Consultations may include plastic surgery for cleft palate, orthopedics for limb repair, ENT for otitis media and hearing loss, ophthalmology for symptoms related to lacrimal duct hypoplasia, and urology for possible genitourinary malformations.

Extracutaneous findings

Cutis laxa may present in the newborn with skin changes, joint laxity, and abdominal and inguinal hernias. Pulmonary emphysema may develop either during childhood or later in the course of the disease.¹⁰⁹ In X-linked cutis laxa, bladder and gastrointestinal diverticuli can occur. Many newborns present with congenital dislocation of the hip. The characteristic long-bone and occipital exostoses (occipital horns) occur over time. Autosomal recessive disease is often more severe than the other forms, with flaccid skin evident at birth, early-onset emphysema, and vascular abnormalities such as aortic aneurysms or pulmonary artery/valve stenosis.¹⁰⁹ Death from complications related to emphysema may occur early in infancy. The autosomal dominant form typically has fewer internal manifestations and a normal associated lifespan.¹¹⁰

Etiology and pathogenesis

The inherited forms of cutis laxa are detailed in Table 29.4.

Differential diagnosis

Ehlers–Danlos syndrome (EDS) has similar skin laxity, but has the elastic recoil lacking in cutis laxa. Unlike in EDS, vascular fragility and problems with wound healing are lacking. Cutis laxa may also present as a component of other genetic disorders. Acquired cutis laxa is often late onset and associated with drug exposure to penicillin, d-penicillamine, or isoniazid. Alternatively, acquired disease may develop from crops of well-demarcated inflammatory plaques in association with fever, malaise, and peripheral neutrophilia or eosinophilia.¹¹¹ This form, which has sometimes been called ‘Marshall syndrome’ has been reported in infancy.¹¹² Areas of loose wrinkled skin are also evident in the so-called ‘prune belly syndrome’ where lax skin is seen in association with renal anomalies and hypoplastic abdominal musculature (Fig. 29.16).¹¹³

The diagnosis is confirmed by elastin staining (Verhoeff–van Gieson, orcein) of a skin biopsy. X-linked disease has abnormally large collagen fibrils with normal elastic fibers, whereas autosomal disease has reduced elastin, an abnormal dense amorphous component, and variation in collagen fibril diameter with collagen ‘flowers.’ Low serum ceruloplasmin or copper levels may also help in the diagnosis of affected boys.¹⁰⁹

Treatment and care

All patients should have a complete physical examination for associated abnormalities, chest radiography to screen for emphysema and cardiomyopathy, and echocardiography for potential cardiac valve involvement (Box 29.9). Pulmonary function tests should be considered for early detection of emphysema. As solar elastosis aggravates cutaneous disease, sun protection should be emphasized.¹¹⁴ Early parenteral copper-histidine replacement may prolong life and delay the onset of symptoms in patients with the X-linked form.¹¹⁵

Cutaneous findings

Babies with the classic type of EDS have soft, velvety, extensible skin that feels doughy and is very fragile with bruising and splitting secondary to minimal trauma. Wounds are slow to heal, quickly dehisce, and often resolve with cigarette paper-like atrophic scars. Patients with kyphoscoliosis-type and arthrochalasia-type EDS have less prominent skin fragility, bruisability, and dermal hyperextensibility than those with classic EDS.¹¹⁷ Patients with the periodontal form have similar skin findings to those in classic EDS, but additionally have excessive wrinkling of the palms and soles. Over time, the skin becomes hyperpigmented and markedly atrophic. In dermatosparaxis-type EDS a patient’s skin is characterized by extreme fragility and is sagging, redundant, and not in-elastic.

Rather than having the extensible and doughy skin seen in classic EDS, the skin in vascular-type EDS is thin and translucent with a visible vascular pattern (Fig. 29.17). It is not fragile and heals normally, but bruising is still common. Patients have a typical facial appearance, characterized by a thin nose, thin lips, and prominent eyes. Unless the disorder is already known to be in the family, none of these features is likely to be appreciated in the newborn or young infant.

Extracutaneous findings

Of the neonates with EDS, 40% are delivered prematurely.¹²² All forms of EDS have joint hypermobility with joint dislocations; congenital dislocation of the hip occurs in the classic, vascular, and arthrochalasia types. Although the prevalence is unknown, cardiac and aortic abnormalities seem to be much more common than in the general population. This is most evident in patients with the vascular type of EDS, who are at high risk for rupture of medium-sized arteries, aorta, and bowel, either spontaneously or following minor trauma. Special precautions should be taken when performing surgery on these patients.

Etiology and pathogenesis

The pathogenesis and inheritance patterns of EDS are detailed in Table 29.5.

Differential diagnosis

Cutis laxa also has hyperextensible skin, but it is loose and sagging, whereas the skin in EDS is elastic and recoils. Although patients with Marfan syndrome may also have mild to moderate joint hypermobility, the skin in newborns with Marfan syndrome does not show distinctive findings in this age group as it may with EDS.

Treatment and care

Treatment of EDS is mostly supportive and preventative (Box 29.10). Large doses of ascorbic acid (a cofactor of lysyl hydroxylase), 2–4 g/day, have been used in patients with kyphoscoliosis-type EDS, with clinical response.¹²³ Specific therapies are not routinely used in other subtypes, although some physicians recommend high-dose ascorbic acid for all subtypes.¹²⁴

A cardiovascular examination should be performed on all patients. Those with evidence of abnormalities or any patient with the vascular form of EDS should have an echocardiogram (Box 29.10). Alternatively, some recommend echocardiography at diagnosis for all patients, to assess aortic size.¹¹⁷

Because of tissue friability, surgical procedures are difficult, with dehiscence and wound breakdown being common. Although scars will still spread over time, a combination of adhesive tape, skin closure surgical adhesive tape, absorbable running subcuticular suturing, increased density of sutures, or cyanoacrylate adhesives may facilitate healing. Pseudotumor formation may be prevented by applying pressure bandages to hematomas. Parents should be instructed on how to protect the infant from trauma.

Extracutaneous findings

After skin disease, skeletal abnormalities constitute the second most constant manifestation of FDH and include limb reduction, asymmetric growth, small stature, and split-hand/split-foot malformations (‘lobster-claw’ deformity).¹²⁷ Vertical striations in the metaphyses of long bones (osteopathia striata) may be seen in many patients and are a useful index for diagnosis.^130,131 Ocular abnormalities affect approximately 40% of patients and range from strabismus to microphthalmia.¹²⁷ Teeth are commonly malformed or absent. Less commonly described findings include clavicular anomalies, abdominal wall defects, renal anomalies, and congenital heart defects.^127,132,133

Etiology and pathogenesis

FDH is X-linked dominant and presumed lethal in hemizygous males. It is due to mutations in the PORCN gene which encodes a protein important in Wnt signaling.^134,135 Lyonization of the X chromosome may explain the cutaneous Blaschko linear distribution. Rare cases in males may arise from somatic mosaicism and half-chromatid mutations.¹³³

Differential diagnosis

The diagnosis of FDH is clinical, with histologic and radiographic corroboration (see above). Skin lesions of FDH do not blister and are static in comparison with IP. There is no epiphyseal stippling in FDH as in Conradi–Hunermann–Happle syndrome (X-linked dominant chondrodysplasia punctata), which also has linear ichthyosis and follicular atrophoderma as opposed to the telangiectases, hypo-/hyperpigmentation, and/or dermal atrophy of FDH. Distal extremities are not involved in MIDAS (microphthalmia, dermal aplasia, and sclerocornea) syndrome, and herniations of fatty tissue are not found. The initial skin changes of linear porokeratosis and porokeratotic eccrine and ostial dermal duct nevus may also resemble FDH, but evolution over time and histopathology can help to distinguish these conditions.

Treatment and care

After a complete physical examination looking for possible systemic manifestations, the management of FDH is mainly symptomatic. Infants should be evaluated by dermatology, ophthalmology, and orthopedic surgery as needed because of the common occurrence of skeletal, cutaneous, and ophthalmologic disease. Other anomalies should be investigated in symptomatic individuals.

Cutaneous findings

Absent tearing, a cardinal feature of Riley–Day syndrome, is usually not appreciated in neonates, as overflow tearing does not develop until 2–3 months of age in normal infants. Affected babies may have striking blotching and mottling of the skin. This usually appears one month after birth and within the first year, as do bouts of hyperpyrexia. Emotional excitement often precipitates the appearance of red blotches. The hands and feet may be cool and mottled from vasoconstriction, or swollen and red from vasodilation. In familial dysautonomia, indifference or insensitivity to pain results in progressive self-mutilation, burns, and ulcers. Absent fungiform papillae on the tip of the tongue are an important diagnostic feature and the associated absence of taste buds leads to decreased ability to taste, especially sweetness. Insensitivity to pain causes oro-dental-self-mutilation of the tongue, lips and cheeks or loss of teeth. Compulsive biting in those areas may cause tumor-like masses called Riga–Fede disease (see Fig. 30.14), or ulcers. In toddlers, injuries to the tongue from emerging teeth are common.

Extracutaneous findings

Although usually not diagnosed until several years of age, generalized signs appear within the newborn period in over 80% of patients.¹⁶⁵ These signs include breech birth in one-quarter, prematurity, intrauterine growth retardation, hypotonia, respiratory insufficiency, and poor feeding with swallowing difficulty and aspiration, developmental delay, short stature, scoliosis and corneal disease. Unexplained episodes called ‘dysautonomic crises’ of fever, labile blood pressure, tachycardia, aspiration pneumonia, and vomiting are typical. Deep tendon reflexes are invariably absent. Dysmorphic facial features are not associated, but facial asymmetry and a straightened mouth develop due to abnormal tone and molding of the facial bones.¹⁶³

Etiology and pathogenesis

The causative gene for familial dysautonomia syndrome is the IKBKAP (I-kappa-B kinase complex associated protein) gene on chromosome 9q31. Disease expression is variable even though 99.5% of affected children have the same homozygous mutations.¹⁶⁶ The cause is decreased survival of certain sensory, sympathetic, and parasympathetic nerve cells.

Differential diagnosis

In an infant with unexplained hyperpyrexia, abnormal sweating, and failure to thrive, the primary differential diagnosis is hypohidrotic ectodermal dysplasia versus familial dysautonomia syndrome. Injection of histamine (1 : 10 000) does not elicit a flare response in familial dysautonomia. The flare response can discriminate between the two conditions, as can the presence of teeth on a Panorex examination of the jaw. Further, in familial dysautonomia, the pupil is hypersensitive to parasympathomimetic drops like methacholine and pilocarpine. Upon exposure, the pupil almost always shrinks in familial dysautonomia, but not in a normal eye. The astute physician, aware of the feature of random blotching and mottling of the skin, may be able to make the diagnosis of Riley–Day syndrome in an infant whose multiplicity of problems have eluded correct diagnosis.

Treatment and care

Due to poor coordination, breast-feeding is difficult and delivery of proper nutrition might require a nasogastric tube or possible gastrostomy tube in the first year.¹⁶³ Use of artificial tears, and avoidance of aspiration are necessary. Referral to neurology and orthopedics for specialized care is recommended. The involvement of multiple subspecialists in addition to close follow-up with the primary care provider is important.