Brachydactyly type E in two sibs with increased bone density and mental retardation. A new autosomal recessive syndrome?

Brachydactyly type E in two sibs with increased bone density and mental retardation. A new autosomal recessive syndrome?: We report on two sibs, a boy and a girl, with syndromic brachydactyly type E. Parents were first cousins. Facial dysmorphia was characterized by a flat occiput, a large forehead, hypertelorism, a long triangular nose, an everted lower lip, downslanting palpebral fissures and strabismus. They had marked shortening of the third, fourth and fifth fingers and of the third, fourth, and fifth toes. IQ was 16 in the boy, 63 in the girl. In both sibs ophtalmologic examination showed strabismus, absence of cataract and normal fundus and radiological findings disclosed increased bone density involving the skull, the vertebrae and the corticalis of the long bones. Neither ectopic calcifications, nor exostosic, nor osteomalacia, and nor osteotis fibrosa cystica were present. Investigations revealed that plasma calcium, phosphate, vitamine D, parathyroid hormone (PTH), response to exogenous PTH, and Gs activity were normal as well as renal and thyroid function. Molecular genetic studies failed to identify mutations in the GNAS 1 gene, in the PTH receptor gene and in the HOX D13 gene. Analysis of 2q showed that there was no deletion 2q37. Other known syndromes with brachydactyly type E and mental retardation were excluded. In conclusion we suggest that these two sibs with a combination of brachydactyly, mental retardation and increased bone density have a specific autosomal recessive syndrome.     

Familial occurrence of a syndrome with mental retardation,nasal hypoplasia,peripheral dysostosis,and blue eyes in Japanese siblings

Summary Two Japanese siblings, a 2-year-old girl and a 7-month-old boy, had a syndrome of mental retardation, severe nasal hypoplasia, peripheral dysostosis, and blue eyes. The mother showed nasal hypoplasia of lesser degree and a mild form of peripheral dysostosis. This disorder bears a striking similarity to acrodysostosis, but in view of certain novel features its relationship to the disease is uncertain. The mode of inheritance could be either dominant with variable expressivity or autosomal recessive.     

Hypoparathyroidism-retardation-dysmorphism syndrome

Congenital hypoparathyroidism, growth retardation and facial dysmorphism is a rare autosomal recessive disorder seen among children born to consanguineous couple of Arab ethnicity. This syndrome is commonly known as Sanjad-Sakati or hypoparathyroidism-retardation-dysmorphism syndrome (HRD). We report 13-year-old Hindu boy with hypoparathyroidism, tetany, facial dysmorphism and developmental delay, compatible with HRD syndrome.     

Dysmorphic face in two siblings with infantile neuroaxonal dystrophy

Infantile neuroaxonal dystrophy (INAD) is an autosomal recessive, neurodegenerative disease with onset in the first or second year of life. It has been reported that INAD shows numerous phenotype characteristics including problems associated with vision, hearing and physical coordination. It has however been very rare to see facial dysmorphism in these children. The study analyzes a girl and boy of a first cousin marriage with infantile neuroaxonal dystrophy affected at birth. At infancy, the children were examined in the Cerrahpa?a Medical Faculty Genetic Research Center, Istanbul. They had typical INAD features such as the lack of head control, vision, speech, sitting, and walking which are also seen in children with other congenital abnormalities. These children showed remarkable dysmorphism in the face which included prominent forehead, strabismus, small nose, fish mouth (boy), micrognathia, and large and low-settled ears. The presence of these facial features makes the patients appear unique and diagnosis more accurate. While these features are commonly seen diagnosis may be difficult at its onset. Until now this appearence has not been reported in INAD patients. In conclusion, in the first few months of life without any clinical or neurological signs, the physician should also consider diagnosing the disease of the infant as INAD.     

Tau syndrome (thrombocytopenia and absent ulnar) with mental retardation and facial dysmorphy.

A girl with pancytopenia (hemoglobin 9 g. 2,000 PMN. 75,000 platelets) was examined at 23 years of age. She had microcephaly, facial dysmorphy, skeletal deformities (kypho-scoliosis, club feet, club hands) and mental retardation. Puberty was normal, Roentgenograms showed bilateral agenesia of the distal part of the ulna with dislocation of the head of the radius. No other skeletal parts were absent. The condition is probably due to an autosomal recessive gene, the parents being second cousins.     

Severe hypophosphatasia due to mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene

Hypophosphatasia is a rare autosomal recessive inborn error of metabolism characterized by a defective bone mineralisation and deficiency of serum and tissue liver/bone/kidney alkaline phosphatase activity. We report the characterisation of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutation in a patient affected by infantile hypophosphatasia. This boy was the first child of non affected, non related parents. At 1 month of age he presented with palsy of the left upper limb with hypotonia. Length was - 2SD. The anterior fontanel was large. There was a markedly decreased ossification of all bones. All limbs were shortened. Ultrasonographic examination of the kidneys showed nephrocalcinosis. Level of alkaline phosphatases was decreased in the child as well as in the parents. Bone density was decreased. At 2 years of age development was delayed. Weight was - 3,5 SD and OFC - 3SD. The child had craniosynostosis. Molecular studies showed 2 missense mutations, both in exon 6 of the TNSALP gene.     

Fryns anophthalmia-plus syndrome with hypoplastic adrenal glands

We report a family with two consequent sibs with anophthalmia and cleft lip and palate. A 27 year old woman married to her first cousin was counseled for anophthalmia and cleft lip and palate detected during routine fetal ultrasonographic examination on the 23rd week of the pregnancy. Her obstetric history revealed a healthy girl aged 7 years and a boy with anophthalmia and cleft lip and palate who lived for 20 days in the neonatal intensive care unit. The current pregnancy was terminated after the diagnosis, and post mortem examination of the fetus revealed pre-maxilla agenesis, anophthalmia, cerebral ventricular dilatation, adrenal hypoplasia and single umbilical artery. Chromosome analysis resulted in normal karyotypes of the fetus and both parents. The inheritance pattern was regarded as autosomal recessive and the family was informed about the condition and risks during genetic counseling.     

A Turkish case of subcortical/subependymal heterotopia associated with corpus callosum dysgenesis, craniofacial dysmorphism, severe eye abnormalities, and growth-mental retardation

The patient is a 12-year-old boy with a history of learning disability, growth retardation, and strabismus. Weight, height and head circumference were below the 3rd percentile. A café-au-lait spot, 1x1 cm a diameter, on the back region and pectus excavatum deformity were diagnosed. He had facial asymmetry, a broad nose, sparse eyebrows and eyelashes, a rudimentary frontal sinus, deviation of the nasal septum, and bilateral small maxillary bones. The left orbital fossa was also mildly rudimentary. On eye examination the movements of the left globe to the upward and lateral side were limited and internal strabismus was noted at this side. Visual acuity was 1/10, bilaterally. Bilateral choroid coloboma, glaucoma, vertical and horizontal nystagmus were diagnosed. Fundoscopic examination revealed bilateral optic atrophy and macular and paramacular granulation tissues on the left side. Intelligence quotient was 46. Electroencephalography revealed bilateral frontal slow-wave activity. Visual evoked potential revealed prolonged p100 wave latencies bilaterally. Magnetic resonance imaging of the brain demonstrated corpus callosum dysgenesis, bilateral subcortical heterotopia in the frontal lobes and subependymal heterotopia in the posterior horn of the left ventricle. Chromosomal analysis revealed a normal male karyotype, 46, XY. Although several cases of heterotopia in association with mental retardation, craniofacial dysmorphism, cerebral, and eye abnormalities have been described the combination of abnormalities diagnosed in our case has not previously been reported. We hypothesize that the combination of subcortical/subependymal heterotopia, corpus callosum dysgenesis, craniofacial dysmorphism, severe eye abnormalities, and growth-mental retardation may be a new syndrome.     

Progeroid syndrome with facial teleangiectatic erythema, posterior subcapsular cataracts, calcification of basal ganglia and atrium septum defect type 2

In this report we present the long-term follow-up findings in a young female born to consanguineous parents with the unique association of (1) a progeroid syndrome, (2) facial dysmorphism with relative microcephaly, triangular face, retrognathism and skin erythema, (3) bilateral posterior cataracts, (4) basal ganglia calcifications and (5) atrium septum defect type 2. Intelligence is borderline. Clinical evolution after normal puberty was positive with regression of the facial erythematous changes. Over the years differential diagnosis included progeria, hypohidrotic ectodermal dysplasia, Rothmund-Thompson syndrome, Cockayne syndrome, Bloom syndrome, but the clinical spectrum of abnormalities and the evolution with age were not compatible with one of these diagnoses. Parental consanguinity is in favour of autosomal recessive inheritance.     

Gingival fibromatosis, short stature, border-line IQ, facial dysmorphism and hepatomegaly

Gingival fibromatosis, short stature, border-line IQ, facial dysmorphism and hepatomegaly: Gingival fibromatosis is a rare and benign disorder. The enlarged gingivae are firm and may interfere with speech, closure of the lips, and mastication. We report a thirteen years old girl, with gingival fibromatosis referred to the periodontics clinics. Full mouth gingivectomy and gingivoplasty were performed. Medical investigation showed short stature, low-borderline IQ, facial dysmorphism, and hepatomegaly. Histological analysis revealed hyperplasia in the epithelial area and fibrotic appearance of gingival connective tissue with dense collagen fibre clusters. Pedigree analysis confirmed that mode of inheritance is autosomal recessive. According to the combination of clinical findings, this case report may represent a previously unreported syndrome.     

Do we consider Andermann syndrome in infants with agenesis of corpus callosum

Andermann syndrome is characterized by agenesis of corpus callosum, anterior horn cell disease, a mixed sensory and motor neuropathy, and facial dysmorphism, and is inherited as an autosomal recessive trait. A 7-month-old boy was admitted with developmental retardation. Head control was not gained and he could not sit. He had high arched palate, elongated facies and large angle of the mandible, which were compatible with the Andermann syndrome. Moderate hypotonicity and absent tendon reflexes were also noted. Serum creatine kinase level was normal. Magnetic resonance imaging of the brain showed agenesis of the corpus callosum. Electromyographic examination revealed the presence of both sensory and motor neuropathy. The patient was diagnosed as having the Andermann syndrome according to the clinical and laboratory findings and he is reported due to rare presentation.     

Hypogonadotropic hypogonadism due to GnRH receptor mutation in a sibling

Hypogonadotropic hypogonadism (HH) is characterised by delayed puberty and infertility. Congenital HH comprises Kallmann syndrome with hypo-/anosmia and idiopathic HH (IHH). The genetic origin remains unknown in most cases, but the defective GnRH receptor gene (GNRHR) accounts for a considerable proportion of IHH. Here we describe a pair of siblings diagnosed with IHH. Aged 17 years, the boy was referred because of short stature (162 cm) and overweight (62.5 kg). He presented no signs of puberty, bone age of 14.5 years and insulin resistance. His sister, aged 16 years, also displayed delayed puberty. She was 166 cm tall and weighed 52 kg; her bone age was 12.5 years. Pelvic ultrasonography showed an infantile uterus and fibrous ovaries. In both siblings, serum gonadotropins were extremely low, and non-responsive to GnRH. Testosterone (1.38 nmol/l) and IGF1 (273 ng/ml) were decreased in the boy, although the girl did not present IFG1 deficiency. Her serum oestradiol was 10 pg/ml. MRIs of the hypothalamo-pituitary region and olfactory bulbs revealed them to be normal. The patients' sense of smell was unaltered. Their parents appeared to be first degree cousins. Considering the clinical data and potentially autosomal recessive HH transmission, the GNRHR gene was screened. The siblings turned out to be homozygous for the G416A transition, which had previously been identified in other HH individuals. The parents were heterozygous mutation carriers. The proband, moderately responding to LH, was started on low dose testosterone replacement, and his sister on transdermal oestradiol. Molecular data indicative of GnRH resistance could guide their future therapy should they desire fertility restoration. Further observations of the male patient may provide insights into androgen's influence on body mass, growth and insulin sensitivity.     

A sibship with hypervalinemia

Summary During routine screening of amino-acid disorders, we detected hypervalinemia in two sibs (a girl of 4 and a boy of 3 years of age) of a consanguineous marriage. There was no excess accumulation or excretion of leucine or isoleucine, which presumably indicates the absence of valine tranxaminase.     

Male pseudohermaphroditism with persistent müllerian structures, mental retardation and Borjeson-Forssman-Lehmann-like features: a new syndrome?

We report two sibs with an undescribed MCA/MR syndrome. Both had a 46,XY chromosome constitution. The first patient is profoundly mentally retarded. Clinical features include short stature, coarse face, deep set eyes, microphthalmia, large ears, gynecoid obesity, imperforate anus, sacral spina bifida, pseudovaginal perineoscrotal hypospadias, persistence of Müllerian structures, and low gonadotrophin levels. His XY sib was raised as a girl. She was slightly mentally impaired. She had microphthalmia and large ears, and was short. A complete uterus with tubae and a single intraabdominal gonad with testicular organization were removed during infancy. Those anomalies do not fit any previously reported syndrome, although the general aspect of the propositus clearly resembles Borjeson-Forssman-Lehmann syndrome. Inheritance could be either autosomal recessive or X-linked.     

Intercalary deletions of 9q]

Two interstitial deletions of different segments of 9q are reported. The first deletion (9/11q22) was seen in an 8-year-old boy with severe psychomotor retardation and descrete facial dysmorphism. The second deletion (9q32q34) was seen in a 5-month-old boy with a very peculiar cranio-facial dysmorphism including brachycephaly, frontal bossing, a deep nasal bridge, a short nose, and absence of triradii b, c and d.     

A syndrome of congenital ichthyosis, hypogonadism, small stature, facial dysmorphism, scoliosis and myogenic dystrophy

Rud syndrome formerly was considered as a genetically heterogeneous but distinct clinical entity with the manifestations of ichtyosis, hypogonadism, small stature, mental retardation, epilepsy and, infrequently, retinitis pigmentosa. The existence of such a syndrome has recently been dismissed based on a new understanding of the ichthyoses. We report on the clinical history of a 14-year-old boy with congenital ichthyosis, small stature, hypogonadism, facial dysmorphism, nystagmus, kypho-scoliosis and myogenic dystrophy. He was diagnosed as Rud syndrome but developed neither seizures nor mental retardation. However a cousin was mentally retarded. The ichthyosis was familial as five relatives had ichthyosis but no other features of Rud syndrome. The patient had a deletion of the steroid-sulfatase gene. He had neither chondrodysplasia punctata, nor Kallmann syndrome, two conditions which are part of the contiguous gene syndrome of the Xp22.3 region. Most case reports previously reported as Rud syndrome can now be reassigned under a contemporary ichthyosis classification that does not include Rud syndrome as a distinct entity. This case was clearly distinct from Refsum disease, Sj?gren-Larsson syndrome and any of the other ichthyosis disorders that have been suggested as a replacement for Rud syndrome. Thus the case reported here appears distinct from any previously described, currently recognized syndrome.     

Iminoglycinuria — A “harmless” inborn error of metabolism?

Summary A boy with iminoglycinuria was discovered during routine urinary amino acid screening of a series of children with severe visual handicap. In addition to iminoglycinuria and blindness due to Leber's tapeto-retinal degeneration, this boy has profound perceptive deafness dating from infancy. It is concluded, on the basis of a study of previous cases reported, that the iminoglycinuria is not causally related to his blindness and deafness and may represent an essentially harmless inborn error of metabolism. The view that he suffers from three distinct autosomal recessive conditions receives some support from the fact that he may be the offspring of a mating between full sibs.The results reported here are drawn in part from theses submitted by V.M.P. and D.N.W. to the University of Oxford in partial fulfilment of the requirements for the D. Phil. degree.     

Oligodactyly and multiple synostoses of the extremities: Two cases in sibs

Summary Two sibs with a rare phenotype of oligodactyly with metacarpal, carpal, radioulnar, and metatarsal synostoses and shortening of the forearms were born of healthy parents. Genetic counselling with regard to future children of one of these sibs was given on the assumption of an autosomal recessive inheritance, which is highly probable, judging from the other rare familial cases found in the literature.     

A hemizygous GYG2 mutation and Leigh syndrome: a possible link?

Leigh syndrome (LS) is an early-onset progressive neurodegenerative disorder characterized by unique, bilateral neuropathological findings in brainstem, basal ganglia, cerebellum and spinal cord. LS is genetically heterogeneous, with the majority of the causative genes affecting mitochondrial malfunction, and many cases still remain unsolved. Here, we report male sibs affected with LS showing ketonemia, but no marked elevation of lactate and pyruvate. To identify their genetic cause, we performed whole exome sequencing. Candidate variants were narrowed down based on autosomal recessive and X-linked recessive models. Only one hemizygous missense mutation (c.665G>C, p.W222S) in glycogenin-2 (GYG2) (isoform a: NM_001079855) in both affected sibs and a heterozygous change in their mother were identified, being consistent with the X-linked recessive trait. GYG2 encodes glycogenin-2 (GYG2) protein, which plays an important role in the initiation of glycogen synthesis. Based on the structural modeling, the mutation can destabilize the structure and result in protein malfunctioning. Furthermore, in vitro experiments showed mutant GYG2 was unable to undergo the self-glucosylation, which is observed in wild-type GYG2. This is the first report of GYG2 mutation in human, implying a possible link between GYG2 abnormality and LS.     

IMAGe association: additional clinical features and evidence for recessive autosomal inheritance

Congenital adrenal hypoplasia (CAH) normally occurs in the neonatal period, with patients presenting with more or less severe salt-wasting syndrome. X-linked CAH has been associated with mutations in the DAX-1 gene, and boys have also been shown to have hypogonadotrophic hypogonadism. Recently, in three unrelated boys, CAH was associated with intrauterine growth retardation (IUGR), metaphyseal dysplasia and genital abnormalities, defining a new association called IMAGe. We now report four additional patients with this association, including the first living female. The four patients belong to two unrelated families (one brother and one sister from each family). These patients have the main clinical characteristics of IMAGe association: IUGR, facial dysmorphy (frontal bossing, broad nasal bridge, low-set ears), short limbs due to metaphyseal dysplasia, and adrenal insufficiency. As these patients are older than the initial three patients, we can also describe additional features: short adult height, normal puberty in boys as well as in the living girl. The boys have hypospadias associated with micropenis. The living girl came to clinical attention at the age of 5 years as a result of a familial survey, and careful questioning revealed that she had been suffering from mild adrenal insufficiency since early childhood. At least one boy has congenital hypotonia due to muscular dystrophy. In conclusion, these four new cases display familial transmission, strongly suggesting Mendelian autosomal recessive inheritance. Adrenal insufficiency may be mild. Hypotonia, described in all the patients, might be related to paucisymptomatic muscular dystrophy, as this condition is clearly heterogeneous varying with regard to severity, associated manifestations and outcome. If this symptom is part of the syndrome, which we cannot assume, it could help to localize the candidate gene.