Stephanie Spranger

Ehlers-Danlos Syndrome Type VII: Clinical Features and Molecular Defects*

We evaluated the clinical features, molecular defects, and problems associated with the management of two patients who had type-VII Ehlers-Danlos syndrome and reviewed the cases of eighteen patients with this condition who had been reported on previously. The typical clinical features associated with this syndrome include bilateral congenital dislocation of the hip; severe generalized hypermobility of the joints; multiple dislocations of joints other than the hip; muscular hypotonia; and hyperelasticity, fragility, and a doughy texture of the skin. Collagen and DNA analyses demonstrated that both of our patients had type-VIIB Ehlers-Danlos syndrome, which is caused by heterozygous new mutations of the COL1A2 gene that encodes the proalpha2(I) chain of type-I procollagen. The obligatory GT dinucleotide at the splice donor site of intron 6 was altered in both of our patients: one patient (Case 1) had an A substitution of the G nucleotide, and the other patient (Case 2) had a C substitution of the T nucleotide. Abnormal splicing resulted in the loss of the exon 6-encoded N-telopeptide, which includes the N-proteinase cleavage site. Despite multiple operative procedures, one of our patients, who was thirty-seven years old at the time of the most recent follow-up, continued to have persistent subluxation of the right hip and osteoarthritis of the left hip. Closed reduction of the dislocated hips, regardless of the type of immobilization used, was unsuccessful in all twenty patients. The results of open reduction were improved when capsulorrhaphy was combined with iliac or femoral osteotomy, or both.

Familial Hemiplegic Migraine with Cerebellar Ataxia and Paroxysmal Psychosis

Familial hemiplegic migraine is a rare autosomal dominant disorder associated with stereotypic neurologic aura phenomena including hemiparesis. So far two chromosomal loci have been identified. Families linked to the chromosome 19 locus display missense mutations within the CACNL1A4 gene. Here we report on a family with familial hemiplegic migraine and cerebellar ataxia with recurrent episodes of acute paranoid psychosis with anxiety and visual hallucinations associated with migraine attacks. Based on the clinical and haplotype evidence indicating linkage to chromosome 19 in this family, we hypothesize that a dysfunction of the mutated calcium channel may be involved not only in the development of hemiplegic migraine but also in the acute psychotic episodes observed in these patients.

Molecular studies of an X;Y translocation chromosome in a woman with deletion of the pseudoautosomal region but normal height

A translocation chromosome in a woman with the karyotype 46,X,der(X)t(X;Y)(p22.3; q11.2) was investigated by FISH and STS analysis with molecular probes derived from the sex chromosomes. Due to the partial deletion of the short arm pseudoautosomal region (PARI) from DXYS14 to DXYS147 in the translocation chromosome, the proband is hemizygous for the gene responsible for growth control (SS) located in this region, yet does not show growth retardation. Molecular analysis of the Yq arm of the translocation chromosome revealed the presence of markers DYS273 to DYS246 harboring the hypothesized growth control gene critical region (GCY) on Yq, thereby placing the deletion breakpoint between markers DYS11 and DYS273. These results suggest that the Y‐specific growth gene GCY on Yq compensates for the missing growth gene SS on Xp22.3.

Köbberling-Dunnigan syndrome: a rare cause of generalized muscular hypertrophy.

A 36‐year‐old woman presented with muscle hypertrophy (particularly of the calves) since puberty, occasional muscle cramps, a musculine habitus, and a loss of subcutaneous fat on limbs and trunk sparing her face, neck, and vulva. Multiple lipomas were found on her trunk, and acanthosis nigricans on her neck. Laboratory testing revealed hyperlipidemia and pathological glucose tolerance with hyperinsulinemia. Physical and laboratory findings are consistent with Köbberling‐Dunnigan syndrome, a rare inherited form of lipoatrophy. The patients mother had the same body habitus and insulin‐dependent diabetes mellitus. These cases suggest that partial lipodystrophy also affects muscle and is a cause of genuine muscular hypertrophy.

Barraquer-Simons syndrome (with sensorineural deafness): a contribution to the differential diagnosis of lipodystrophy syndromes.

Among the lipodystrophies, the Barraquer-Simons syndrome is a rare condition. We describe a 27-year-old woman with progressive loss of subcutaneous fat after 15 years first affecting the face and spreading to the upper part of the body. She also suffered from deafness and had marked changes in cranial MRI. We discuss possible differential diagnosis such as the Cockayne, SHORT and Berardinelli-Seip syndrome.

MIDAS-Syndrom – Eine X-chromosomale Erkrankung Differentialdiagnose zum kongenitalen Varizellensyndrom

ZusammenfassungHautdefekte in segmentaler Anordnung und Mikrophthalmus sind Leitsymptome des kongenitalen Varizellensyndroms. Ein genetisch bedingtes Krankheitsbild, das MIDAS-Syndrom (MI=Mikrophthalmus; DA=dermal aplasia; S=Sklerokornea), hat eine ähnliche klinische Symptomatik. Dieser Erkrankung liegt eine terminale Deletion des kurzen Arms des X-Chromosoms im Bereich Xp 22.3 zugrunde. Diskussion: Wir stellen das Krankheitsbild anhand eines Falls vor und diskutieren weitere Differentialdiagnosen wie das Aicardi- und das Goltz-Gorlin-Syndrom.SummaryPatients with congenital varicella syndrome develop cicatricial skin lesions and microphthalmia. An overlap in the clinical manifestations exist with a specific genetic disorder, called MIDAS syndrome. It is due to a partial deletion of the short arm from chromosome X, with consecutive monosomy Xp22.3. Discussion: We discuss the phenotype and possible differential diagnosis such as Aicardi syndrome and Goltz-Gorlin syndrome.

Ehlers-Danlos Syndrome Type VIII and Leukodystrophy

and 111, or ultrastructural abnormalities of skin fibroblasts and extracellular ma- trix, have not been demonstrated [Dyne et al., 19931. The collagen bundle architecture appears normal [Hol- lister, 19821. Diagnosis is based on clinical findings in- cluding early periodontal disease, ecchymotic pretibial lesions, minimal bruising, and premature aging [Stewart et al., 1977; Linch and Acton, 1979; Steinmann et al., 19931. We describe a case of EDS VIII with addi- tional cerebral involvement. This 37-year-old woman is the second of three chil- dren born to non-consanguineous parents. Her father did not have premature loss of teeth but rather delayed healing of superficial wounds with cigarette-paper skin over the anterior tibial ridges. Her mother and two brothers were healthy. The patient noticed ecchymoses following slight trauma since age 8 years, but no epi- sodes of severe or prolonged bleeding. After age 10 years, the alveolar ridges of the man- dible degenerated progressively with loss of all teeth. At 15 years she also lost all maxillary teeth except two. After puberty, she complained of severe headache and several episodes of drop-attacks without loss of con- sciousness or other neurologic deficits. Since age 20 years repeated swelling of fingers and toes occurred independent of menstruation; she suffered from hy- permenorrhoe. Her body measurements were normal: height 165 cm, weight 70 kg, and head circumference 57 cm (all 50th-75th centile). Her face gave the im- pression of premature aging. Gingival recession and gingivitis were present. A mottled brown skin rash was distributed over the trunk. The skin over the tibial crest was extremely thin and brownish. Hypermobility of joints, hyperextensibility of skin, and contractures were absent. The neurological findings were normal, in- cluding intellectual performance. Laboratory evaluation including normal alkaline phosphatase and urinary phospho-ethanolamine excre- tion excluded hypophosphatasia which may also lead to

Bilateral radial deficiency with lower limb involvement

We describe a 10-month-old boy with an unclassified form of radial aplasia with absent thumbs, tibia hypo/-aplasia, and partial absence of toes. Only a few cases with similar limb deficiencies have been published. We try to classify the malformations on the basis of embryological considerations and discuss possible differential diagnosis.

Three familial cases presenting with an immobile spine. Rigid spine or Emery-Dreifuss syndrome ?

A father and his two sons presented with slowly progressive muscular weakness, contractures of the spine, elbows and ankles, and cardiac conduction disturbances in the father. Clinical and histological findings are discussed in relation to the hitherto reported cases of autosomal dominant variant of the Emery‐Dreifuss syndrome and the distinction from the rigid spine syndrome.

Das klinische Spektrum des Holt-Oram-Syndroms

Skelettfehlbildungen und Herzfehler sind Leitsymptome des autosomal dominant erblichen Holt-Oram-Syndroms. Bei vollständiger Penetranz kann der Ausprägungsgrad der klinischen Symptome innerhalb einer Familie jedoch sehr unterschiedlich sein und zu diagnostischen Schwierigkeiten führen.Anhand von 13 eigenen Patienten mit Holt-Oram-Syndrom im Alter 1–35 Jahren wird das klinische Spektrum dargestellt. Es reicht von - meist asymmetrischen - Phokomelien der oberen Extremität bis zu isolierten Thenarhypoplasie als Minimalsymptom der Erkrankung.Eltern eines scheinbar sporadischen Falles sollten gezielt daraufhin untersucht werden, um das Wiederholungsrisiko für weitere Kinder bestimmen zu können.