Genotype-phenotype correlations emerging from the identification of missense mutations in MBTPS2.

Missense mutations affecting membrane-bound transcription factor protease site 2 (MBTPS2) have been associated with Ichthyosis Follicularis with Atrichia and Photophobia (IFAP) syndrome with or without BRESHECK syndrome, with keratosis follicularis spinulosa decalvans, and Olmsted syndrome. This metalloprotease activates, by intramembranous trimming in conjunction with the protease MBTPS1, regulatory factors involved in sterol control of transcription and in cellular stress response. In this study, 11 different MBTPS2 missense mutations detected in patients from 13 unrelated families were correlated with the clinical phenotype, with their effect on cellular growth in media without lipids, and their potential role for sterol control of transcription. Seven variants were novel [c.774C>G (p.I258M); c.758G>C (p.G253A); c.686T>C (p.F229S); c.1427T>C (p.L476S); c.1430A>T (p.D477V); c.1499G>A (p.G500D); c.1538T>C (p.L513P)], four had previously been reported in unrelated sibships [c.261G>A (p.M87I); c.1286G>A (p.R429H); c.1424T>C (p.F475S); c.1523A>G (p.N508S)]. In the enzyme, the mutations cluster in transmembrane domains. Amino-acid exchanges near the active site are more detrimental to functionality of the enzyme and, clinically, associated with more severe phenotypes. In male patients, a genotype-phenotype correlation begins to emerge, linking the site of the mutation in MBTPS2 with the clinical outcome described as IFAP syndrome with or without BRESHECK syndrome, keratosis follicularis spinulosa decalvans, X-linked, Olmsted syndrome, or possibly further X-linked traits with an oculocutaneous component.

A novel mutation in the PORCN gene underlying a case of almost unilateral focal dermal hypoplasia.

BACKGROUND: Focal dermal hypoplasia (also known as Goltz syndrome) is an X-linked dominant syndrome characterized by patchy hypoplastic skin with soft-tissue, skeletal, dental, and ocular defects that are secondary to mutations in the PORCN gene. To our knowledge, only 5 cases of focal dermal hypoplasia with unilateral presentation have been reported, and molecular studies were not performed in any of the cases. OBSERVATIONS: A 17-year-old girl was seen with features of almost unilateral focal dermal hypoplasia. These included left cleft hand, dental dysplasia, left mammary hypoplasia, deviation of the sacral line, raspberrylike papillomas in the perianal region, syndactyly of the second and third digits of the left foot, and linear streaks of dermal hypoplasia and pigmented lesions on her left hemibody. CONCLUSIONS: Mutation analysis of PORCN revealed a novel heterozygous mutation in exon 10, c.854-855insACCTGAC; [p.T285fsX316], resulting in a premature stop signal. Analysis of the X-chromosome inactivation status was performed on blood and skin DNA samples, showing random inactivation in blood and unaffected skin and skewed inactivation in affected skin, highlighting the role of X-chromosome inactivation in X-linked disease expression.

Neonatal rhabdomyosarcoma misdiagnosed as a congenital hemangioma.

Highly vascularized malignant soft-tissue tumors can clinically and radiologically mimic deep hemangiomas. We present a case of congenital rhabdomyosarcoma of the neck, which was initially identified as congenital hemangioma.

Two observations raising questions about risk factors of cutaneous necrosis induced by terlipressin (Glypressin).

INTRODUCTION: Triglycyl lysine vasopressin (terlipressin, Glypressin) is a potent vasoconstrictive drug which became popular because of its prolonged duration of action, ease of administration and lower incidence of side effects. Ischemic complications are rare but may be life threatening. OBSERVATIONS: Case 1, a 68-year-old man with alcoholic cirrhosis and hepatocellular carcinoma, was admitted due to acute functional renal failure. He was first treated for septic shock with intravenous catecholamines. He then developed hepatorenal syndrome and received terlipressin as intravenous bolus (4 mg/day). Three days later, he presented a diffuse purpuric and necrotic eruption with tongue ischemia. He died from Staphylococcus aureus infection. Case 2, a 74-year-old man with metastatic carcinoma, presented severe renal insufficiency. He developed sepsis and pseudohepatorenal syndrome, which was treated with terlipressin (0.5 mg/h) using an infusion pump. Four days later, he developed an isolated large erythematous and purpuric macular plaque of the scalp near skin metastases. The patient died a few weeks later from tumor progression. In both cases, skin biopsies showed ischemic necrosis caused by thrombosis of superficial dermal capillaries. CONCLUSION: These cases point to the risk of either widespread or localized necrosis. Although the precise incidence of these events as well as risk factors remain to be determined, hypovolemia, concomitant administration of vasoactive drugs and the mode of administration of terlipressin may influence the occurrence of these complications.

Unusual presentation of a severe autosomal recessive anhydrotic ectodermal dysplasia with a novel mutation in the EDAR gene.

We report on an 18-year-old woman, born to first-cousin parents, presenting with a severe form of anhydrotic ectodermal dysplasia (EDA/HED). She had sparse hair, absent limb hair, absent sweating, episodes of hyperpyrexia, important hypodontia, and hyperconvex nails. She also showed unusual clinical manifestations such as an absence of breasts, a rudimentary extranumerary areola and nipple on the left side, and marked palmo-plantar hyperkeratosis. Light microscopy of skin biopsies showed orthokeratotic hyperkeratosis and absence of sweat glands. A novel homozygous mutation (IVS9 + 1G > A) in the EDAR gene was identified. This mutation results in a total absence of EDAR transcripts and consequently of the EDAR protein, which likely results in abolition of all ectodysplasin-mediated NF-kappaB signaling. This is the first complete loss-of-function mutation in the EDAR gene reported to date, which may explain the unusual presentation of HED in this patient, enlarging the clinical spectrum linked to the dysfunction of the ectodysplasin mediated NF-kappaB signaling.

Mutation in WNT10A is associated with an autosomal recessive ectodermal dysplasia: the odonto-onycho-dermal dysplasia.

Odonto-onycho-dermal dysplasia is a rare autosomal recessive syndrome in which the presenting phenotype is dry hair, severe hypodontia, smooth tongue with marked reduction of fungiform and filiform papillae, onychodysplasia, keratoderma and hyperhidrosis of palms and soles, and hyperkeratosis of the skin. We studied three consanguineous Lebanese Muslim Shiite families that included six individuals affected with odonto-onycho-dermal dysplasia. Using a homozygosity-mapping strategy, we assigned the disease locus to an ~9-cM region at chromosome 2q35-q36.2, located between markers rs16853834 and D2S353, with a maximum multipoint LOD score of 5.7. Screening of candidate genes in this region led us to identify the same c.697G-->T (p.Glu233X) homozygous nonsense mutation in exon 3 of the WNT10A gene in all patients. At the protein level, the mutation is predicted to result in a premature truncated protein of 232 aa instead of 417 aa. This is the first report to our knowledge of a human phenotype resulting from a mutation in WNT10A, and it is the first demonstration of an ectodermal dysplasia caused by an altered WNT signaling pathway, expanding the list of WNT-related diseases.

Further delineation of the odonto-onycho-dermal dysplasia syndrome.

We report on three boys, two brothers and their maternal cousin, presenting with dry hair, pilar keratosis, severe hypodontia, smooth tongue, onychodysplasia, and keratoderma and hyperhidrosis of palms and soles. Histology of the skin showed orthokeratotic, hyperkeratosis, hypergranulosis, and mild acanthosis in the epidermis. Scanning electron microscopic examination of the hair showed longitudinal depressions in some hair. These features are close to a rare entity: the odonto-onycho-dermal dysplasia but with some differing features.

New autosomal recessive syndrome with short stature and facio-auriculo-thoracic malformations.

Two sibs, a boy and a girl, from a Lebanese consanguineous family presented with short stature, microcephaly, ptosis, small, dysplastic, low set ears, short neck, and pectum excavatum and carinatum. In addition, the boy had a high arched palate, a cardiac malformation, and at the X-rays an absence of fusion of the posterior hemi-arches of C7 and a fusion between L5 and S1 with a sagittal-cleft vertebral body of L5, while his sister had a cleft lip/palate and at the X-rays an abnormal odontoid peg and a malformation of the articular facets between C1 and C2, and bilateral cervical ribs. Other laboratory and radiological investigations were normal. Sequencing of PTPN11 exons 2, 3, 4, 7, 8, 12, and 13 did not reveal any variations. Two other sibs presented almost the same dysmorphic features; one girl died at age 6(1/4) years after an acute episode of renal insufficiency, and one boy died at 40 days of age. Differential diagnosis is discussed and the possibility of the report of a new autosomal recessive syndrome with variable expressivity is raised.