The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis.

The Comèl-Netherton syndrome is an autosomal recessive multisystemic disorder characterized by localized or generalized congenital ichthyosis, hair shaft abnormalities, immune deficiency, and markedly elevated IgE levels. Life-threatening complications during infancy include temperature and electrolyte imbalance, recurrent infections, and failure to thrive. To study the clinical presentations of the Comèl-Netherton syndrome and its molecular cause, we ascertained 19 unrelated families of various ethnic backgrounds. Results of initial linkage studies mapped the Comèl-Netherton syndrome in 12 multiplex families to a 12 cM interval on 5q32, thus confirming genetic homogeneity of Comèl-Netherton syndrome across families of different origins. The Comèl-Netherton syndrome region harbors the SPINK5 gene, which encodes a multidomain serine protease inhibitor (LEKTI) predominantly expressed in epithelial and lymphoid tissues. Recently, recessive mutations in SPINK5 were identified in several Comèl-Netherton syndrome patients from consanguineous families. We used heteroduplex analysis followed by direct DNA sequencing to screen all 33 exons and flanking intronic sequences of SPINK5 in the affected individuals of our cohort. Mutation analysis revealed 17 distinct mutations, 15 of which were novel, segregating in 14 Comèl-Netherton syndrome families. The nucleotide changes included four non-sense mutations, eight small deletions or insertions leading to frameshift, and five splice site defects, all of which are expected to result in premature terminated or altered translation of SPINK5. Almost half of the mutations clustered between exons 2 and 8, including two recurrent mutations. Genotype-phenotype correlations suggested that homozygous nucleotide changes resulting in early truncation of LEKT1 are associated with a severe phenotype. For the first time, we used molecular data to perform prenatal testing, thus demonstrating the feasibility of molecular diagnosis in the Comèl-Netherton syndrome.

Lymphedema as a postulated cause of cutis verticis gyrata in Turner syndrome.

Unusual skin lesions were present at birth in four infants with Turner syndrome. The skin changes in these patients appear to have resulted either from in utero entrapment or pinching of edematous skin or from redundant skin remaining after in utero resolution of lymphedema. Distention by lymphedema is thought to cause several of the phenotypic characteristics seen in patients with Turner syndrome, including nuchal webbing and nail changes. In three of these patients the clinical appearance of the skin changes was similar to cutis verticis gyrata, marked by fixed thickened plaques in folds.

Diet and atopic dermatitis.

Prevention or modification of the onset of atopic dermatitis has been difficult to document through prolonged breast feeding or delayed introduction of solid foods. Dietary management of established atopic dermatitis is not routinely indicated for the majority of patients. Dietary management of atopic dermatitis should not be continued indefinitely. Gradual reintroduction of the offending food(s) is often appropriate. The foods most commonly avoided in the management of atopic dermatitis are cow's milk, wheat, eggs, and nuts. Severe or prolonged dietary restrictions should not be instituted without full consideration of their impact on the patient's general health.

The vascular lesions of childhood.

A wide array of vascular lesions occurs in the pediatric population. The lesions vary in nature from normal physiologic phenomena to large vascular malformations with serious and sometimes life-threatening complications. Vascular lesions occur in 20 to 40 per cent of newborn infants and therefore comprise the single largest group of neoplasms in infancy and childhood. Specific entities are discussed in two major sections--hemangiomas and vascular stains.

Cutaneous histiocytosis syndromes.

Cutaneous histiocytosis may take two principal forms. It is either a benign proliferative process or a relentless, progressive process with a poor prognosis. In histiocytic medullary reticulosis, histiocytes demonstrate nuclear atypia and the outcome is uniformly fatal. Benign cephalic histiocytosis X causes lesions similar to those of histiocytosis X, but Langerhans' cells are absent. In congenital self-healing histiocytosis X, the Letterer-Siwe-like cutaneous infiltrate contains Langerhans' cells, but the lesions heal spontaneously without treatment. The nodular cutaneous lesions of juvenile xanthogranuloma appear in infancy and resolve without treatment; however, the higher percentage (10%) of associated ocular lesions may lead to glaucoma and blindness. In histiocytosis X, the cutaneous lesions show a marked proliferation of Langerhans' cells, with prognosis dependent on the patient's age and the extent of organ dysfunction. Patients who survive the acute form of the disease may develop diabetes insipidus, growth retardation, pulmonary fibrosis, and biliary cirrhosis. A subtle immunologic defect has been identified in patients with histiocytosis X, yet the pathogenesis of the disease is still speculative. Familial disease occurring in early infancy should be differentiated from complete or partial immunodeficiency syndromes. Guidelines for evaluating patients with cutaneous histiocytosis are reviewed.

Lupus erythematosus in neonates, children, and adolescents.

Neonatal LE should be suspected in any infant with an erythematous or scaling dermatitis, especially if it is distributed on the head and neck or if there is a history of photosensitivity. It should also be suspected in any infant with congenital heart block. A biopsy, though helpful, is not necessary since the diagnostic abnormality is the presence of anti-Ro(SSA) antibodies in infant's serum. When the disease is diagnosed, the infant can be effectively treated with a mild topical steroid and sun avoidance, with or without sun-screens, until the age of 12 months when the autoantibodies have presumably degraded. The child then should be observed periodically through adulthood for the onset of SLE. Mothers of infants with neonatal LE need to be checked for the presence of anti-Ro antibodies and SLE, Sjögren's syndrome, or thyroiditis. The recurrence of neonatal LE in some, but not all, future pregnancies must be anticipated. As more of these infants are followed into adulthood, we will learn how often neonatal LE is a marker for adult-onset SLE.

Congenital generalized fibromatosis: a review of the literature and report of a case associated with porencephaly, hemiatrophy, and cutis marmorata telangiectatica congenita.

In congenital generalized fibromatosis (CGF), fibrous nodules involve the skin, bone, and viscera, and the mortality rate is as high as 80% because the visceral nodules can significantly obstruct and compress vital organs. If the fibromas involve only the skin and skeleton and not the viscera, the disease is known as congenital multiple fibromatosis, and the prognosis is excellent. In both conditions, which may be variants of the same disease process, the fibromas resolve completely and spontaneously. There are no previous reports in the literature of CGF associated with cutis marmorata telangiectatica congenita (CMTC), hemiatrophy, or porencephaly with hemiparesis, although CMTC has been seen in conjunction with hemiatrophy. These associations may be coincidental.