Cutaneous findings

The most frequent cutaneous presentation – particularly in infants and newborns – consists of multiple widespread vesiculopustules with umbilication and a hemorrhagic crust.^18–23 Lesions tend to favor the scalp, trunk, diaper area, and skin folds (Fig. 28.2A). They may begin as subtle brown or pink papules, and evolve into crusted or purpuric lesions (Fig. 28.2B). Papular lesions may coalesce into areas of superficial ulceration with oozing, especially in intertriginous areas. Characteristic lesions also include fissures behind the ears, and crusting and oozing of the external ear canals. The scalp is a frequent site of involvement, and the coalescence of crusted and scaling lesions may lead to partial alopecia. Presentation as a ‘blueberry muffin baby,’ with cutaneous hematopoiesis, has been reported.²⁴ Nodules and petechiae, which may involve the palms and soles, are also observed. Oral lesions are relatively common, and can develop before skin lesions. They may appear as superficial ulcerations or erosions, but these are often associated with underlying alveolar bone disease. Other oral manifestations include gingival bleeding, facial swelling, and pain. Premature eruption and loss of teeth, and destruction of alveolar bone are characteristic. Involvement of the vulva and vagina may also occur. Nail involvement consists of subungual pustules, paronychia, onycholysis, and longitudinal grooving. Permanent nail dystrophy may result.²⁵

Extracutaneous findings

The majority of infants with all forms of congenital or neonatal Langerhans’ cell histiocytosis will show evidence of multisystem disease.^31–33 Bone lesions are the most frequent noncutaneous manifestation. Findings may include asymptomatic lytic lesions, deformation, fracture, or medullary compression. The skull is a common site, and disease in that location manifests on X-ray as punched-out lesions in the cranial vault. Mastoid involvement may lead to mastoid necrosis, and destruction of the ossicles may result in deafness. Intercranial disease may cause exophthalmos and diabetes insipidus. Lymph node involvement is seen in a significant percentage of patients, and tends to occur in the cervical chain. Pulmonary disease may be associated with cough and tachypnea. Other findings include bullae formation and diffuse interstitial fibrosis. Invasion of the liver may cause mild cholestasis, but eventually evolve to sclerosing cholangitis. Severe fibrosis of the liver results in ascites, jaundice, and liver failure. Involvement of the spleen may worsen the severity of thrombocytopenia. Gastrointestinal disease is reported to occur in a small percentage of patients.³⁴ Characteristic findings are vomiting, diarrhea, protein-losing enteropathy, and failure to thrive secondary to malabsorption. The most common endocrine manifestation is diabetes insipidus. This occurs most often in children with extensive disease and involvement of the skull. Langerhans’ cells may also infiltrate the thyroid and pancreas.

Diagnosis

Biopsy of a cutaneous lesion reveals a diffuse infiltration of histiocytes with abundant eosinophilic cytoplasm and eccentric, indented nuclei. In some cases, the nuclei may appear pleomorphic or atypical. Positive CD1a and/or CD207 (Langerin) staining of the lesional cells is needed for a definitive diagnosis. Electron microscopy is no longer required since it is now known that the expression of Langerin correlates with the ultrastructural presence of Birbeck granules.³⁵

Preliminary laboratory evaluation of the patient with biopsy-proven skin lesions must include a complete blood count (CBC), serum electrolytes, urine specific gravity, and assessment of liver function. Examination of the bone marrow may show the presence of increased histiocytes. Skeletal survey, chest radiographs, and magnetic resonance imaging (MRI) may be used to determine the extent of bone, pulmonary, liver, spleen, and CNS involvement.

Differential diagnosis

The pustular and intertriginous lesions of LCH in neonates and infants may be confused with candidiasis, seborrheic dermatitis, psoriasis and scabies. Congenital LCH must also be differentiated from other neoplastic disorders, such as leukemia and lymphoma; from congenital infections, especially herpes simplex; and from those viral disorders associated with ‘blueberry muffin’ lesions.

Treatment and course

The majority of children with infantile LCH develop multisystem disease. The prognosis seems to be better in congenital ‘self-healing’ LCH, but multisystem disease is still possible, and such neonates must be followed to assure that they do not develop extracutaneous disease later on. Survival of infantile LCH in the past few decades has improved from 57% to 74%.^16,35 Single-system disease has a significantly higher rate of survival (94%), but patients with initial liver involvement have a much poorer prognosis, with a 25% 5-year survival. In children with LCH limited to the skin (<5% of cases), a ‘wait and see’ approach should be accompanied by careful monitoring for disease progression. Children in this category may benefit from therapy with mild to moderate-strength topical corticosteroids. Children with multisystem disease are treated with chemotherapy; standard treatment is based on steroids and vinblastine.

Primary cutaneous anaplastic large cell lymphoma

This form of cutaneous T-cell lymphoma is characterized by large tumor cells that express CD30 antigen. Clinical presentations consists of papules, and plaques which may ulcerate. The rare occurrence of this disease during the first 2 years of life has been documented.³⁷

Lymphomatoid papulosis

Lymphomatoid papulosis is a chronic, recurrent disorder characterized by the presence of reddish brown papules and nodules. Progression to malignant forms of lymphoma is rarely reported. In one series of pediatric patients, including children under the age of 2 years, a benign course, accompanied by a predominance of CD8+ lymphocytes was observed.³⁸

Cutaneous B-cell lymphoma

Primary cutaneous B-cell lymphoma is extremely rare in infancy. Primary cutaneous lymphoblastic lymphoma, presenting with firm violaceous nodules with overlying telangiectasia, has been reported to occur in some children under the age of 2 years.^39,40 Subcutaneous panniculitis-like T-cell lymphoma, with purplish tender nodules in an acral distribution, has also been reported to occur in infancy.^41,42

Cutaneous findings

Fibrosarcoma most often presents as a soft tissue mass, sometimes with rapid growth. The overlying skin may be tense, shiny, and erythematous, and ulceration may occur (Fig. 28.6).⁴⁷

Diagnosis

MRI is useful in defining the extent of the lesion, but the diagnosis is largely based on histology. Histologic examination reveals a highly cellular fibroblastic proliferation, with sizeable vascular clefts and occasional myxoid degeneration and hemorrhagic necrosis.⁴⁸ Analysis of the biopsy sample for the recurrent translocation t(12;15)(p13;q25) is highly recommended.⁴⁹

Differential diagnosis

Clinically, infantile fibrosarcomas are easily confused with either hemangiomas or vascular/lymphatic malformations.^50,51 Transient consumptive coagulopathy mimicking Kasabach–Merritt phenomenon has been reported, causing confusion with other vascular tumors (see Chapters 21 and 22).⁵² The differential diagnosis also includes rhabdomyosarcoma and infantile myofibromatosis.

Treatment and course

The risk of metastasis, especially in cutaneous lesions, is considerably lower in infants (approx. 8%) than in older patients.⁵³ Treatment consists of wide local excision. Chemotherapy has been used in some patients to reduce the lesion mass preoperatively so as to avoid the need for mutilating surgery, and for lesions that are not resectable.⁵⁴ Close follow-up to monitor for the presence of local recurrence and metastatic disease, is mandatory.⁵⁵

Cutaneous findings

Characteristically, DFSP begins as an atrophic plaque surrounded by an area of bluish discoloration. Over time, as the cellular proliferation extends into the deep dermis and subcutaneous tissues, nodules develop on the plaque surface (Fig. 28.8). Similar to the lesions seen in older patients, congenital DFSP occurs most commonly on the trunk and proximal extremities.⁵⁹ Giant cell fibroblastoma more typically presents during infancy as a slow-growing soft-tissue mass.

Diagnosis

Histologically, DFSP is characterized by the presence of spindle cells in a well-defined and uniform storiform pattern. Focal myxoid change and scarring may occur. Tumor cells express vimentin, but are negative for S100 protein, epithelial membrane antigen, and smooth muscle actin.⁶⁰ Diagnosis can be facilitated by detection of the collagen type Iα1/platelet-derived growth factor β-chain fusion gene by means of reverse transcriptase–polymerase chain reaction or fluorescence in situ hybridization.⁵⁸

Differential diagnosis

Clinically, the differential diagnosis of congenital DFSP includes fibrous hamartoma of infancy, infantile myofibromatosis, lipoblastoma (see Chapter 27), and vascular tumors and malformations. Neurofibroma and fibrous histiocytoma may mimic DFSP histologically.

Treatment

Because of the high risk of recurrence, adequate surgical margins must be obtained. Mohs micrographic surgery is the preferred approach in older children. However, in young infants, this can be difficult to arrange logistically in a child requiring general anesthesia for the excision, so wide excision is generally performed.⁶¹

Extracutaneous findings

Metastatic disease, characterized by fever, hepatomegaly, and failure to thrive, is often present at the time of diagnosis. The primary lesion is usually located in the upper abdomen, arising within the adrenal gland, and may be detected as an enlarging mass.

Diagnosis

Diagnosis of the cutaneous lesions is based on histologic examination. The dermal or subcutaneous infiltrate consists of small cells with scanty cytoplasm and heterochromatic nuclei. Pseudorosettes and mature ganglion cells are present in differentiated lesions. Immunoperoxidase staining may establish the presence of neuron-specific proteins.

Although most cases of neuroblastoma are sporadic, autosomal dominant inheritance may occur. Concordance in monozygotic twins has also been reported.⁶⁵ The location and extent of the primary lesion is most often established by computed tomography (CT) or MRI. Increased urinary catecholamines are present in the majority of patients.

Differential diagnosis

Clinically and histologically, the lesions of neuroblastoma must be differentiated from leukemia and lymphoma. In addition, the blueberry muffin appearance of some lesions may mimic congenital rubella or cytomegalovirus infection.

Treatment and course

The prognosis of neuroblastoma depends on the age of the patient and the extent of the disease (stages 1–4S). The survival rate at 2 years in children who are diagnosed under the age of 1 year exceeds 80%. In some patients, especially with stage 4S, spontaneous differentiation to neural ganglion cells and regression without treatment have been reported. The choice of treatment depends on staging and patient age, and consists of various combinations of surgery, radiation therapy, and chemotherapy.⁶⁶

Extracutaneous findings in mast cell disease

Most infants with MIS do not have evidence of extracutaneous disease, but the risk increases with extent of cutaneous disease or symptoms such as flushing or recurrent diarrhea. Outside of the skin, the bone marrow is most often affected. Mast cell hyperplasia in lymph nodes, spleen, liver, bone or GI tract occurs rarely.⁹³ Associated symptoms in infants is variable and commensurate with local or systemic MC-mediator release or organ dysfunction from MC infiltration of organs. Signs and symptoms include diarrhea, vomiting, abdominal pain, bone pain, headache, hypotension, and shock. Prolonged bleeding in the skin and GI tract may occur, and is more frequent in infants with DCM. In these children, heparin from mast cells acts as a local anticoagulant. Elevated levels of circulating histamine, which stimulates gastric acid secretion, may result in gastric ulceration and gastrointestinal hemorrhage.⁹⁴ Children with DCM have the highest incidence of visceral mast cell disease and associated systemic manifestations. MPCM in infants is rarely associated with visceral involvement, and visceral involvement does not appear to occur in children with solitary mastocytomas. The incidence of allergic disease is not increased in children with mastocytosis, but the severity of allergic reactions is increased and the risk of anaphylactoid reactions (e.g., to hymenoptera stings) is also increased.

Serum tryptase level is the best screening test for extracutaneous disease in the setting of extensive cutaneous disease or signs or symptoms of more widespread disease. If serum tryptase is persistently elevated (i.e., >20 ng/ml with normal being ~5 ng/ml) and systemic mastocytosis is clinically suspected, bone marrow evaluation should be considered.⁹⁵ The optimal cutoff for baseline serum tryptase levels in children with MIS that predict the need for daily anti-mediator therapy, hospitalization, and ICU management is 15.5 ng/ml, and 30.8 ng/ml respectively (for sensitivity and specificity of 100% and 95%, and 100% and 96%, respectively).^96,97

Etiology and pathogenesis

The cause of mastocytosis is unknown. However, activating mutations in the c-kit proto-oncogene have been identified in many patients, more so in adult than childhood cases. C-kit encodes for KIT, the membrane receptor for stem cell factor, and is expressed on mast cells, melanocytes, and hematopoietic stem cells. These mutations likely contribute to the characteristic proliferation of mast cells and hyperpigmentation of the skin seen in cutaneous mastocytosis, as well as the myeloproliferative diseases observed in some patients with mastocytosis.⁹⁸

Diagnosis

The clinical presentation and characteristic cutaneous lesions usually allow for easy diagnosis. Skin biopsy should be performed when the diagnosis is unclear or when bullae are the main feature. Histopathologic criteria for the diagnosis of MIS include the presence of large clusters (15 cells each) of MCs or scattered MCs exceeding 20 cells per high-power (×40) field.⁹⁹ Toluidine blue, Giemsa or MC-specific stains for c-kit (CD117) and tryptase can assist with identification of MCs. Bullae, when present, are subepidermal. Baseline serum tryptase levels, which tend to correlate with BSA involvement, may be useful in predicting infants at high risk of serious systemic symptoms.⁹⁴ Clinical evidence of extracutaneous mastocytosis should guide any additional diagnostic studies (ultrasound, bone and liver/spleen scans, GI endoscopy, skeletal survey, and bone marrow evaluation).¹⁰⁰ The usefulness of studies performed empirically is limited, and they do not appear to provide any prognostic information.⁸⁷

Differential diagnosis

Mastocytomas should be differentiated from xanthomas, juvenile xanthogranulomas, café-au-lait macules and congenital nevi. Infestation with Sarcoptes scabei presenting with pruritic, red-brown nodules that exhibit a Darier’s sign may be mistaken for mastocytosis. Differentiating characteristics include more severe pruritus, lack of other lesions with other morphologies (e.g., paucity of macules and plaques commonly observed with MPCM), and distribution favoring covered and intertriginous areas in scabetic nodules.¹⁰¹ Where bullae are prominent or lesions are atypical, biopsy is indicated to differentiate mastocytosis from the immunobullous diseases, epidermolysis bullosa, or other infiltrative disorders (see Chapter 11).

Treatment and care

There is no curative treatment for pediatric mastocytosis, however the course in most cases is benign and the prognosis generally favorable. Solitary mastocytomas have not been reported to progress to systemic involvement.¹⁰⁰ More than 50% of childhood cases of MPCM/UP resolve by adolescence, and the remainder experience a marked reduction in cutaneous symptoms.^91,102 Of the patients whose disease persists into adulthood, 15–30% develop indolent systemic involvement, which is similar to the rate observed in adult-onset disease.⁹¹ Children presenting with congenital bullous MPCM or DCM have a higher risk for sudden death, usually from circulatory collapse.¹⁰³

Treatment is aimed at reducing pruritus and, in some children, minimizing blister formation. The regular use of H₁ antihistamines such as hydroxyzine or cetirizine is effective in treating pruritus, bullae, flushing, and abdominal pain. The addition of H₂ blockers and oral disodium cromoglycate may be effective for patients with gastrointestinal signs or symptoms.^104–106

Cutaneous mastocytomas may be treated with a short course of ultra-potent topical steroids or topical calcineurin inhibitors, and very problematic lesions may be excised. Rare instances of circulatory collapse as a result of systemic histamine release should be treated with careful fluid management and intravenous epinephrine.¹⁰⁶ A self-injectable epinephrine device may be prescribed for children with a history of such episodes.⁸⁷ PUVA therapy is effective for severe forms of MIS.¹⁰⁷ Aggressive forms of MC respond partially to interferon-α or cladribine and there are positive anecdotal reports using tyrosine kinase inhibitors.⁹⁵ Parents should be provided with a list of substances that potentially stimulate mast cell activity and which should therefore be avoided or given with caution (Box 28.1).⁹⁰

Cutaneous findings

Several distinct characteristic skin lesions are observed in JHF. Small, skin-colored, pearly papules are found predominantly on the ears, neck, and paranasal folds, where they may coalesce to form thin plaques (Fig. 28.15A). Translucent-appearing larger papules and nodules are found around the nose, behind the ears, and on the tips of digits. These may have a gelatinous consistency. Papillomatous perianal lesions, resembling condylomata, have been observed in some patients.¹⁰⁸

Extracutaneous findings

The most consistent and earliest extracutaneous manifestation of JHF is joint flexion contracture, especially of the knees and elbows. Many patients become severely disabled by these progressively severe contractures. Ultrasound evaluation of affected joints reveals distinctive alterations such as irregular cortical surface of MCPs and PIPs, osteophytes and bone erosions, and increased synovial fluid, even in infancy.¹⁰⁹ Gingival hypertrophy is seen in nearly all patients, and the majority have osteolytic bone lesions and osteoporosis.¹¹⁰ JHF generally does not involve the viscera; however, there is considerable clinical and histologic overlap with the more severe disease of infantile systemic hyalinosis (ISH). In ISH, there are hyaline deposits in multiple organs, recurrent infections, often persistent diarrhea, and death within the first 2 years of life.¹⁰⁸ Intellectual development is normal at both ends of the spectrum.

Etiology and pathogenesis

JHF and ISD are caused by mutations in the gene encoding capillary morphogenesis protein-2 (CMG-2), an integrin-like cell surface receptor for laminins and type IV collagen.^111,112 The nature of the hyaline deposition is still not clear but may be composed of increased type VI and decreased type I collagen.¹¹³ On routine histology, the dermal papules show thinning of the epidermis and a dermis occupied by abundant, amorphous, PAS-positive, diastase-resistant material containing wavy filamentous elements. Cells with oval or spindle-shaped nuclei are embedded in this stroma, imparting a chondroid appearance. These fibroblastic cells often display PAS-positive cytoplasmic vacuoles. Ultrastructurally, the fibroblastic stromal cells display a hyperplastic and dilated rough endoplasmic reticulum with collections of smooth-surfaced cisternae filled with tangled microfilaments.¹⁰⁸ Osteoporosis and osteolytic bone lesions are observed on radiographic examination of most patients. Routine laboratory evaluations are normal.

Differential diagnosis

The differential diagnosis should first include Winchester syndrome, a rare autosomal recessive condition that has many overlapping features with JHF, including joint contractures, dwarfism, hypertrophic lips and gingivae, severe osteoporosis, thickened leathery skin, and corneal opacities.¹¹⁴ Lipoid proteinosis may be distinguished from JHF by a distinctly different histology, a characteristic hoarse cry, and a more benign clinical course.

Treatment and course

The course is progressive. Excluding those most severely affected with hyaline material in the viscera, most patients survive into adulthood with severe physical deformities due to joint contractures, delayed motor development, and skin nodules that recur after surgical excision. Treatment, which is unsatisfactory, includes excision of skin lesions, repeated gingivectomy, and systemic corticosteroids for joint symptoms. At least one patient has been treated with interferon-α, with some reduction and softening of the smaller fibromas only (Ruiz-Maldonado and Duran, pers comm).

Cutaneous findings

The characteristic cutaneous features include multiple subcutaneous nodules, flesh-colored papules, nodules, or tumors, especially near joints. Coarse facial features and xanthoma-like papules on the face and hands have also been reported. The resultant granulomatous inflammatory lesions are common findings which may be due to decreased apoptosis of inflammatory cells secondary to increased intracellular ceramide.¹¹⁶

Extracutaneous findings

Painful, deforming joint swelling with restriction of movement, particularly of the distal interphalangeal and metacarpal joints, is characteristic. Infants frequently exhibit marked failure to thrive, recurrent infections, a hoarse cry attributed to laryngomalacia, dyspnea, noisy breathing, and hyperirritability. Impairment of cognitive development, seizures, hepatosplenomegaly, macroglossia, recurrent fevers, and hyporeflexia are variably present.

Etiology and pathogenesis

Farber lipogranulomatosis is caused by a mutation in the gene ASAH1, which encodes for lysosomal acid ceramidase, with resultant progressive accumulation of ceramide in tissues. The characteristic clinical presentation and the detection of low levels of acid ceramidase are diagnostic of Farber disease. Light microscopic examination of skin and other affected tissues is nonspecific, demonstrating foam cells and a granulomatous infiltrate. This inflammation is hypothesized to be due to altered receptor-mediated apoptosis by intracellular ceramide accumulation.¹¹⁷ Several characteristic structures are observed ultramicroscopically, probably resulting from the accumulation of ceramide in cells. Curvilinear tubular bodies (comma-shaped, tubular structures consisting of two single membranes separated by a clear space) are observed in dermal fibroblasts among other affected cells. Banana bodies (variably membrane-bound structures that have a spindle and usually curved shape) are found predominantly in Schwann cells of peripheral nerves.¹¹⁶

Diagnosis

Radiologic examination reveals diffuse osteopenia, underdevelopment of terminal phalanges, and reduced long bone diameters.¹¹⁷ The diagnosis should be confirmed by detection of deficient lysosomal acid ceramidase activity in leukocytes, fibroblasts, or other tissues.

Differential diagnosis

The differential diagnosis includes metabolic storage diseases, particularly other mucolipidoses, malignant histiocytosis, and infantile systemic hyalinosis. Some cases have been misdiagnosed as juvenile rheumatoid arthritis because of the severe joint involvement seen early in the course.

Treatment and course

Most patients die of progressive neurologic deterioration early in the first decade of life. Hematopoietic stem cell transplantation was successfully performed in four patients without CNS involvement (type 2/3 disease), but allogeneic bone marrow transplant failed to halt the progression of Farber disease with CNS involvement (type 1).¹¹⁷ Various other treatments, including corticosteroids and radiotherapy, have been attempted and are ineffective. The potassium–titanyl–phosphate (KTP) laser has been used for treatment of severe oral lesions.¹¹⁸

Because transmission is autosomal recessive, genetic counseling is mandatory. Prenatal diagnosis, performed by assaying acid ceramidase levels in skin cells cultured from amniotic fluid, is now possible.¹¹⁹

Cutaneous findings

The most characteristic cutaneous feature, manifest in all types of MPS, is coarse, thickened skin. This cutaneous alteration combines with underlying craniofacial abnormalities to impart coarse facial features. Patients have a thick nose with a depressed nasal bridge, thick tongue and lips, short neck, and macrocephaly. The severity of the facial abnormalities is variable, and the most striking features are observed in Hurler and Hunter syndromes. Coarse facies may not be present in young infants.¹²² Patients also display variable degrees of coarse hair and generalized hirsutism.

Apart from Sanfilippo syndrome, which presents with synophrys, Hunter syndrome is the only MPS that regularly presents with specific cutaneous findings. Children with Hunter syndrome may develop firm, discrete or coalescing ivory-colored papules on the arms or symmetrically distributed between the angles of the scapulae and the posterior axillary lines. This same finding was described in a patient with Hurler–Scheie syndrome.¹²³ Another finding occasionally reported in Hunter syndrome is usually widespread dermal melanocytosis (see Chapter 24).

Extracutaneous findings

Infants may appear normal at birth, but usually develop characteristic findings in the first few years of life. Each disease has its own array of clinical findings; however, the most important extracutaneous features are mental retardation, deafness, hyperactivity/behavior problems, stiff joints, skeletal dysplasia, kyphoscoliosis, corneal clouding, valvular and coronary heart disease, hepatosplenomegaly, noisy breathing, and lower respiratory tract infections. Table 28.1 lists the cardinal characteristics and pertinent negative findings for each disorder. The skeletal abnormalities in the MPS are referred to as dysostosis multiplex and comprise the following elements: large, thickened skull with premature closure of lambdoid and sagittal sutures; shallow orbits; enlarged J-shaped sellae; and anterior hypoplasia of the lumbar vertebrae. In addition, the long bones display enlarged diaphyses, irregular metaphyses, and poor development of the epiphyseal centers.

Etiology and pathogenesis

Each type of MPS is caused by a deficiency of a specific lysosomal enzyme responsible for the degradation of mucopolysaccharides. This deficiency results in excessive accumulation of the mucopolysaccharides: dermatan sulfate, heparan sulfate, and keratan sulfate throughout the body. The deficient enzyme has been elucidated for each disease, and the genetic loci for several have been mapped.¹²⁴ All have an autosomal recessive inheritance, except for Hunter syndrome, which is X-linked recessive. Excluding an increased incidence of Hunter syndrome in the Jewish population in Israel, and Morquio syndrome in French-Canadians, MPS appear to affect all ethnic groups equally.

Diagnosis

The testing of urine for glycosaminoglycans is the basis for screening patients suspected of having MPS. If screening tests are positive for glycosaminoglycans, a quantitative analysis should be performed to confirm the presence of MPS. The type and quantity of urinary glycosaminoglycans, combined with the child’s clinical presentation, are used to determine the most appropriate enzyme assay to establish definitively the specific type of MPS.¹²⁰ The enzymatic diagnosis should be determined in all patients in whom MPS is suspected. Lysosomal enzyme analysis may be carried out using serum, leukocytes, or cultured cells. In all the MPS, histopathologic examination of skin with Alcian blue, colloidal iron, or Giemsa stain reveals metachromatic granules in fibroblasts, and occasionally in keratinocytes, and in the secretory and ductal cells of eccrine glands. In addition, the cutaneous papules, mostly seen in Hunter syndrome, exhibit extracellular dermal deposits of metachromatic material.¹²⁴

Differential diagnosis

The mucolipidoses are the most important group of diseases to be differentiated from the MPS. I-cell disease (mucolipidosis II) shares most of the clinical features of Hurler syndrome, but patients with I-cell disease do not exhibit urine mucopolysaccharides or acceleration of skeletal growth around 1 year of age.

Treatment, course, and management

The natural course of the more severe forms is progressive, and death resulting from respiratory or cardiac complications often occurs during the second decade. Some types, such as Scheie syndrome, have a normal life expectancy. Bone marrow transplantation lessens the severity and slows the progression of most cases.^121,125 Treatment of patients with MPS I using enzyme replacement therapy with recombinant human α-l-iduronidase reduces lysosomal storage in the liver and levels of urinary glycosaminoglycan excretion, and improves respiratory function and exercise tolerance.^126,127 Because this enzyme does not cross the blood–brain barrier, most likely it will not influence the central nervous manifestations.¹²⁸

Otherwise, management revolves around supportive care. Physical therapy and nighttime splinting may prevent contractures. Special education and frequent audiologic evaluation should be instituted. Many patients benefit from hearing aids. Echocardiograms are recommended to evaluate for valvular abnormalities. Surgical interventions, including corneal transplants for cloudy corneas, cardiac valve replacement, ventriculoperitoneal shunts for communicating hydrocephalus, tracheostomies for obstructive sleep apnea, and occasionally herniorrhaphies, may be helpful. Patients may possess atlantoaxial joint instability imparting an increased risk for spinal injury and paralysis. All patients at risk should undergo careful evaluation, and spinal fusion is recommended for those who are severely affected. Prenatal diagnosis is performed by enzyme assays of cultured amniotic cells, or of cells obtained in chorionic villus sampling.¹²⁹ Prenatal genetic mutational analysis is used less frequently.

Cutaneous findings

The most notable cutaneous findings are the facial features: small orbits and prominent eyes, thickening of the eyelids with a prominent venous pattern, and fullness of the lower face with rounded cheeks. Many small telangiectasias impart a ruddy appearance to the cheeks. Patients often exhibit a fish-mouth appearance in profile as a result of prominent maxillary bones. The neck is short, and the skin has a thickened and rigid texture, particularly on the neck and ears. Gingival hypertrophy, not present in Hurler syndrome, is progressive and severe. At least one patient presented with blueberry muffin rash.¹³⁰

Extracutaneous findings

Neonates commonly exhibit intrauterine growth retardation, with birthweights often below 2500 g. Linear growth is below normal and ceases at 1 year of age. Orthopedic problems manifesting as dysostosis multiplex are common presenting features. Inguinal hernias, especially in boys, may be noted at birth, and patients of both sexes have frequent upper respiratory tract infections and hepatosplenomegaly. All patients experience severe psychomotor retardation, and the majority neither walk unaided nor develop more than primitive language skills. There is progressive stiffness of all joints, first apparent in the shoulders, with decreased mobility by 2 years of age.¹³¹ The long bones of affected infants younger than 6 months display periosteal cloaking, possibly due to repeated new bone formation, and some are born with congenitally short femurs or present with findings suggestive of rickets.¹³² Cone-shaped phalanges and abnormalities of the skull and pelvis are also observed.¹³³

Etiology and pathogenesis

I-cell disease is caused by mutations in the GlcNAc-phosphotransferase alpha/beta gene resulting in defective N-acetyl-glucosamine-1-phosphotransferase, an enzyme involved in the synthesis of a mannose-6-phosphate marker of hydrolases normally found in lysosomes. Because newly synthesized lysosomal enzymes are not marked correctly, the mannose-6-phosphate receptor-dependent transport fails, and the enzymes are secreted out of cells instead of being targeted to lysosomes. This results in failed lysosomal degradation of macromolecules, simulating a catabolic enzyme defect.¹³⁴ Fibroblast lysosomal enzymes are deficient in patients with I-cell disease, whereas the serum levels of the same enzymes are markedly elevated.¹³⁵ The finding that some tissues have normal levels of lysosomal enzymes suggests that there may be an alternative method for targeting lysosomal hydrolases in these tissues.¹³⁶

Diagnosis

The diagnosis of I-cell disease is suggested by detection of an increase in the activity of several hydrolases in plasma. It is confirmed by dermal fibroblast cultures, which show the characteristic cytoplasmic inclusions (I-cells) in the cultured cells. These cytoplasmic inclusions stain positively for PAS and Sudan black, but negatively for Alcian blue, suggesting that the inclusion bodies represent an abnormal accumulation of glycolipid.¹³³ Reduced activity of lysosomal hydrolases in the fibroblasts provides additional confirmation of the diagnosis. Mutational analysis of the GlcNAc-phosphotransferase alpha/beta gene is also possible.

Differential diagnosis

I-cell disease shares most of the clinical features of Hurler syndrome, including coarse facial features, severe psychomotor retardation, and skeletal dysplasia. However, patients with I-cell disease do not exhibit mucopolysaccharides in their urine. Gingival hypertrophy and vacuolated peripheral blood lymphocytes, characteristic of I-cell disease, are not present in Hurler disease.

Treatment and course

Death in early childhood is usually secondary to pulmonary infection or congestive heart failure. Bone marrow transplantation appears to slow neurologic and cardiac progression, but does not alter the skeletal disease.¹³⁷ Because of the recessive inheritance pattern, genetic counseling should be offered. Successful prenatal diagnosis has been accomplished by demonstrating elevated enzyme levels in amniotic fluid in conjunction with enzyme assays from cultured amniotic fluid cells and by electron microscopy showing marked vacuolation in chorionic villus cells.^138,139

Cutaneous findings

The cutaneous lesions are rarely present at birth but tend to occur in the first few years of life. Initially they have varied morphologies, such as erosions, small blisters, crusts and thin papules, which may have features suggestive of impetigo, acne, or varicella. These lesions subsequently develop hypertrophic, and less often atrophic, scarring. Over time the face and trauma-prone sites develop yellowish infiltrated papules and nodules and scarring, reminiscent of cutaneous changes observed with porphyria. Scalp lesions may result in scarring alopecia and significant pruritus can be a problem in some. By about 8 years the majority of patients will display the characteristic small beaded papules along the eyelid margins (moniliform blepharosis) and lips.¹⁴⁰ In addition to these findings, less distinctive firm papules may develop on the neck, armpits, hands, elbows, and knees. Similar lesions may involve the oral mucosa, with resultant loss of teeth and various degrees of ankyloglossia.

Extracutaneous findings

Hoarseness and a weak cry secondary to thickened vocal cords may be present at birth and are usually the first signs of the disease. Even though virtually every organ has been reported to be involved, lipoid proteinosis runs a chronic nonfatal course. Apart from the laryngeal and mucosal involvement, the central nervous system is most commonly affected, resulting in seizures or behavioral changes. Prominent corneal nerves noted with slit lamp examination and confocal microscopy are observed even before moniliform blepharosis.¹⁴¹ Frequently, intracranial calcifications, most often in the temporal lobes, are noted on radiographs from affected individuals.

Etiology and pathogenesis

Pathogenic loss-of-function mutations have been found in the extracellular matrix protein 1 gene (ECM1).¹⁴² The glycoprotein extracellular matrix protein 1 functions in keratinocyte differentiation, basement membrane integrity, and collagen fibril macroassembly. It is recognized also as an autoantigen target in patients with lichen sclerosus et atrophicus.

Diagnosis and differential diagnosis

Routine histology of affected skin demonstrates deposition of amorphous eosinophilic, PAS-positive, hyaline-like material forming concentric rings around microvasculature of the dermis. The mucosa, especially the larynx, and internal organs may likewise be affected. Ultrastructurally, there is disruption and reduplication of the basement membrane around blood vessels and at the dermoepidermal junction. Lipoid proteinosis must first be differentiated from erythropoietic protoporphyria. Lesions in sun-protected and mucosal sites when porphyrin levels are normal assist in this distinction. Other diseases to consider in the differential include papular mucinosis, amyloidosis, cutaneous xanthomas, and leprosy. The rare finding of persistent hoarseness in infancy should be differentiated from congenital hypothyroidism, congenital dysphonia, junctional epidermolysis bullosa, and Farber lipogranulomatosis (see above).

Treatment, course, and management

There is no generally accepted treatment. Mucosal stripping of the vocal cords can temporarily relieve hoarseness, and dermabrasion and CO₂ laser have been performed on skin and vocal cord lesions, respectively.¹⁴³ Dimethyl sulfoxide, d-penicillamine and etretinate therapy have been attempted with varying responses.¹⁴⁴ The overall course is generally benign, with progression throughout childhood and stabilization in early adulthood; therefore supportive care is a rational approach.

Cutaneous findings

Skin lesions can be variable but the typical presentation is that of firm, skin-colored to opalescent papules on the upper arms, dorsal hands and trunk. The lesions can be symmetrical and tightly grouped, linear and in rows, or more generalized. They usually appear soon after birth but can be congenital. Histological findings of lesions demonstrate focal, well-circumscribed deposits of mucin composed of hyaluronic acid (positive stains for Alcian blue at pH 2.5 and colloidal iron) superficially located in the papillary dermis with no evidence of an increase in fibrocytes. A perivascular mononuclear cell infiltrate is also seen in the superficial dermis.

Extracutaneous findings

Laboratory evaluation for paraproteinemia (elevated in scleromyxedema), thyroid function studies (abnormal in myxedema), and autoimmunity are normal or negative. There are no systemic associations typically observed with either CMI or mucinous nevus. One patient with CMI had developmental delay, congenital cataracts, inguinal hernias, and an accessory tragus of unclear etiology.

Etiology and pathogenesis

The etiology and pathogenesis is unknown for CMI.

Diagnosis and differential diagnosis

When congenital CMI needs to be distinguished from the hamartomatous mucinous nevus, it is generally a larger lesion that presents with multiple skin-colored to brownish papules and plaques in a strikingly unilateral Blaschkoid distribution. The histology differs in that there are homogeneous, band-like mucin deposits in the upper portion of the dermis.

Treatment, course, and management

The rarity of CMI precludes any acknowledged treatment re­commendation. However, lesions appear to be unresponsive to high-potency topical corticosteroids or tretinoin cream.

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