Apparently new osteodysplastic and primordial short stature with severe microdontia,opalescent teeth,and rootless molars in two siblings

A Thai man and his sister affected with a newly recognized syndrome of proportionate primordial short stature are reported. The patients had severe intrauterine and postnatal growth retardation, prominent nose and nasal bridge, small pinnae, large sella turcica, areas of hypo‐ and hyperpigmentation of skin, dry and thin scalp hair, and long and straight clavicles. Ivory epiphyses and cone‐shaped epiphyses of the hands were found when they were young, but most of them disappeared as they grew up. Scaphoid and trapezium had angular appearance. The second toes were unusually long. Distal symphalangism of toes and barchymesophalangy of fingers were noted. The findings that appear to distinguish this syndrome from the previously reported syndromes are long second toes, opalescent and rootless teeth, severe microdontia, severely hypoplastic alveolar process, and unerupted tooth. The mode of inheritance is suspected to be autosomal recessive. © 2002 Wiley‐Liss, Inc.     

Microcephalic osteodysplastic primordial dwarfism with severe microdontia and skin anomalies: confirmation of a new syndrome

We report two related Thai children having a new syndrome of microcephalic osteodysplastic primordial dwarfism (MOPD). The findings which classify them as having MOPD include IUGR, microcephaly, prominent nose and nasal bridge, small pinnae, short stature, cone-shaped and ivory-epiphyses, delayed bone age, slender long bones, and abnormal pelvis. The findings that distinguish them as having newly recognized syndrome consist of severe microdontia, malformed teeth, single-rooted or rootless teeth, severely hypoplastic alveolar bone, café au lait spots, acanthosis nigricans, and areas of hypo- and hyperpigmented skin. The reported patients appear to have the same condition as the family reported by Kantaputra [2002: Am J Med Genet 111:420-428]. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299/suppmat/index.html.     

De novo HRAS and KRAS mutations in two siblings with short stature and neuro-cardio-facio-cutaneous features

Mutations in genes involved in Ras signalling cause Noonan syndrome and other disorders characterised by growth disturbances and variable neuro-cardio-facio-cutaneous features. We describe two sisters, 46 and 31 years old, who presented with dysmorphic features, hypotonia, feeding difficulties, retarded growth and psychomotor retardation early in life. The patients were initially diagnosed with Costello syndrome, and autosomal recessive inheritance was assumed. Remarkably, however, we identified a germline HRAS mutation (G12A) in one sister and a germline KRAS mutation (F156L) in her sibling. Both mutations had arisen de novo. The F156L mutant K-Ras protein accumulated in the active, guanosine triphosphate-bound conformation and affected downstream signalling. The patient harbouring this mutation was followed for three decades, and her cardiac hypertrophy gradually normalised. However, she developed severe epilepsy with hippocampal sclerosis and atrophy. The occurrence of distinct de novo mutations adds to variable expressivity and gonadal mosaicism as possible explanations of how an autosomal dominant disease may manifest as an apparently recessive condition.     

Apparently new syndrome of congenital cataracts,sensorineural deafness,Down syndrome-like facial appearance,short stature,and mental retardation

We describe a previously unrecognized syndrome in two unrelated patients with congenital cataracts, sensorineural deafness, distinctive facial appearance, skeletal changes, postnatal short stature, and mental retardation. © 1996 Wiley-Liss, Inc.     

Acrodysplasia, severe ossification abnormalities with short stature, and fibular hypoplasia

We present a girl with short stature, growth hormone neurosecretory dysfunction, severe hypoplastic/aplastic changes of the bones of the hands and feet with dysharmonic ossification, severely delayed bone age, microcrania, and fibular hypoplasia. Parental consanguinity suggests autosomal recessive inheritance. An additional three cases [Eiken et al., 1984: Eur J Pediatr 141: 231-235] sharing some of the radiographic manifestations of this patient have been reported. However, distinctive findings in the present case seem to outline a separate entity.     

A distinctive autosomal recessive syndrome of severe disproportionate short stature with short long bones, brachydactyly, and hypotrichosis in two consanguineous Arab families

Disproportionate short stature is a heterogeneous group of hereditary disorders, which are classified according to their mode of inheritance, their clinical skeletal and non-skeletal manifestations, and their radiological characteristics. Herein, we inform on eight individuals with severe disproportionate short stature from two unrelated consanguineous families of Arab-Muslim ancestry. The adult height of the affected individuals is between 112 cm and 127 cm, and is due to pre- and post-natal growth retardation, which probably manifests as early as the second trimester of pregnancy. At a young age, the phenotype is characterized by a short stature, a relatively large head, and a long triangular face, and this phenotype later evolves to one with in which the head is relatively small, the mandible is large and pointy. The affected individuals have normal cognitive abilities and lack any neurological deficits. Other typical features include a prominent nose, a voice with an unusual high-pitched sound, relatively small ears, clinodactyly, brachydactyly, small hands, hypoplastic fingernails, a waddling gait, and sparse hair post-pubertally. Typical skeletal changes include short long bones, especially the femurs and humeri, with mild metaphyseal changes and very short femoral necks. After due consideration of the other hereditary causes of disproportionate short stature and close examination of the pedigrees of the two families, we concluded that these eight individuals have the same hitherto unreported form of severe disproportionate short stature that is inherited in the autosomal recessive mode.     

Trichothiodystrophy, mental retardation, short stature, ataxia, and gonadal dysfunction in three Moroccan siblings

Three sibs, a boy and two girls, born to Moroccan consanguineous parents, were affected with a syndrome characterized by brittle hair, mental retardation, short stature, ataxia, and gonadal dysfunction. The hair in these three patients displayed the morphological and biochemical hallmarks of trichothiodystrophy (TTD). Gonadal function tests showed abnormal gonadotropic responses to LHRH, consistent with delayed puberty in the male and ovarian failure in both females. Comparison with previously reported cases of TTD associated with mental retardation suggests genetic heterogeneity, although specific biochemical markers are needed in order to answer this question.     

A new syndrome with mental retardation, short stature and an Xq duplication

We describe a new X-linked syndrome of marked short stature, severe intellectual handicap and an unusual facial appearance. High resolution prometaphase banding showed affected males to have an X chromosome tandem duplication; their karyotypes were designated 46,dup(X) (q13.1-q21.1)Y. In carrier females the abnormal X chromosome was late replicating. To verify the duplication, gene dosage studies were performed using an enzyme assay and DNA techniques. Prenatal diagnosis is available for carrier females using chromosome analysis of amniocytes or chorionic villi.     

Split hand malformation, hypospadias, microphthalmia, distinctive face and short stature in two brothers suggest a new syndrome

Split hand/foot malformation (SHFM) is a genetically heterogeneous limb malformation that may be isolated or associated with other malformations. More than 50 recognizable entities with SHFM have been described and at least 5 mapped genetic loci have been implicated. Two brothers with intrauterine growth retardation, short stature, distinctive face, microphthalmia, genital anomalies, and SHFM are described. Molecular analyses of TP63, HOXA13, and HOXD13 genes were normal. We propose this pattern to be a newly recognized SHFM syndrome.     

Four siblings with distal renal tubular acidosis and nephrocalcinosis, neurobehavioral impairment, short stature, and distinctive facial appearance: a possible new autosomal recessive syndrome

We report on four siblings (three males, one female) born to first cousin Arab parents with the constellation of distal renal tubular acidosis (RTA), small kidneys, nephrocalcinosis, neurobehavioral impairment, short stature, and distinctive facial features. They presented with early developmental delay with subsequent severe mental, behavioral and social impairment and autistic-like features. Their facial features are unique with prominent cheeks, well-defined philtrum, large bulbous nose, V-shaped upper lip border, full lower lip, open mouth with protruded tongue, and pits on the ear lobule. All had proteinuria, hypercalciuria, hypercalcemia, and normal anion-gap metabolic acidosis. Renal ultrasound examinations revealed small kidneys, with varying degrees of hyperechogenicity and nephrocalcinosis. Additional findings included dilated ventricles and cerebral demyelination on brain imaging studies. Other than distal RTA, common causes of nephrocalcinosis were excluded. The constellation of features in this family currently likely represents a possibly new autosomal recessive syndrome providing further evidence of heterogeneity of nephrocalcinosis syndromes.     

Biallelic TMEM251 variants in patients with severe skeletal dysplasia and extreme short stature

Skeletal dysplasias are a heterogeneous group of disorders ranging from mild to lethal skeletal defects. We investigated two unrelated families with individuals presenting with a severe skeletal disorder. In family NMD02, affected individuals had a dysostosis multiplex‐like skeletal dysplasia and severe short stature (<?8.5 SD). They manifested increasingly coarse facial features, protruding abdomens, and progressive skeletal changes, reminiscent of mucopolysaccharidosis. The patients gradually lost mobility and the two oldest affected individuals died in their twenties. The affected child in family ID01 had coarse facial features and severe skeletal dysplasia with clinical features similar to mucopolysaccharidosis. She had short stature, craniosynostosis, kyphoscoliosis, and hip‐joint subluxation. She died at the age of 5 years. Whole‐exome sequencing identified two homozygous variants c.133C>T; p.(Arg45Trp) and c.215dupA; p.(Tyr72Ter), respectively, in the two families, affecting an evolutionary conserved gene TMEM251 (NM_001098621.1). Immunofluorescence and confocal studies using human osteosarcoma cells indicated that TMEM251 is localized to the Golgi complex. However, p.Arg45Trp mutant TMEM251 protein was targeted less efficiently and the localization was punctate. Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes. Our work implicates TMEM251 in the pathogenesis of a novel disorder and suggests its potential function in chondrocyte differentiation.     

Severe mental retardation, cataracts, short stature, and primary hypogonadism in two brothers

Two severely mentally retarded brothers are described who had a similar facial appearance, cataracts, short stature, minor digital abnormalities, and primary hypogonadism. Their parents were first cousins. Numerous laboratory investigations failed to elucidate a basic metabolic cause for their disorder.     

Apparently new syndrome of sensorineural hearing loss,retinal pigment epithelium lesions,and discolored teeth

We report on a family with early-onset sensorineural hearing loss, abnormal retinal pigment epithelium granularity, accumulation of creamy-white lesions at the level of the retinal pigment epithelium particularly superior to the arcade, and selective discoloration (brown) of molars or canine deciduous teeth that follows an apparent autosomal recessive inheritance pattern. This appears to be a new syndrome that can be distinguished from the known otodental, oculo-acoustic and flecked retina syndromes by the occurrence of distinct dental and ocular abnormalities. Am. J. Med. Genet. 75:13–17, 1998. © 1998 Wiley-Liss, Inc.     

Skin mastocytosis with short stature, conductive hearing loss and microtia: a new syndrome

A 5 1/2-year-old Sephardic Jewish girl, born of consanguineous parents, is described. She has short stature, microcephaly, conductive hearing loss, skin mastocytosis and microtia. Since this constellation of findings has not been reported previously, we think that these findings represent a new congenital malformation, most probably of genetic etiology.     

GMS syndrome: A new dominant condition with goniodysgenesis,mental retardation,and short stature

We describe a mother and daughter with a distinct phenotype that is different from previous reports. This is likely to constitute a new syndrome for which we propose the mnemonic GMS for G goniodysgenesis, M mental deficiency, and S short stature. The pattern of occurrence is compatible with either autosomal dominant or X-linked inheritance.     

A new syndrome of short stature, joint limitation and muscle hypertrophy

A further case is presented of a new growth deficiency syndrome first reported by Myre et al. in 1981. The major clinical features are mental retardation, growth deficiency, muscular hypertrophy, joint limitation and abnormal skeletal radiography.     

46,XX gonadal dysgenesis, short stature, and recurrent metabolic acidosis in two sisters

Gonadal (ovarian) dysgenesis in 46,XX individuals is genetically heterogeneous. We report on two sisters who, in addition to primary ovarian failure, have marked short stature and recurrent episodes of dehydration with metabolic acidosis. Studies performed during one of these episodes suggested mitochondrial dysfunction; however, results of biochemical analysis of electron transport chain activity in skeletal muscle and mitochondrial DNA studies were normal. We discuss the phenotype in relation to previously described conditions of 46,XX gonadal dysgenesis. We suggest this constellation of findings represents a new syndrome.