High diagnostic yield of clinically unidentifiable syndromic growth disorders by targeted exome sequencing.

BACKGROUND: As syndromic short stature and overgrowth are heterogeneous and the list of causative genes is rapidly expanding, there is an unmet need for identifying genetic causes based on conventional gene testing or karyotyping. Early diagnosis leads to the proper management of the patient and providing genetic counseling for family members at risk in a timely manner. MATERIALS AND METHODS: We conducted targeted exome sequencing to identify the genetic causes of undiagnosed syndromic short stature or overgrowth in 15 pediatric patients from 13 families in Korea. We applied targeted exome sequencing using the Next Seq platform and a TruSight One panel. RESULTS: Among the 13 families, 6 different disorders in 8 patients with short stature or overgrowth were identified, and the diagnostic yield was 46.2%. One boy with overgrowth had a TGFB3 gene mutation. In the short stature group, Coffin-Lowry syndrome (CLS), trichorhinophalangeal syndrome, DYRK1A haploinsufficiency syndrome, short stature with optic atrophy and Pelger-Huët anomaly syndrome with recurrent hepatitis, and type 4 Meier-Gorlin syndrome were identified. One CLS patient had a co-existing monogenic disease, congenital glaucoma, caused by the compound heterozygote mutations of the CYP1B1 gene. CONCLUSION: Targeted exome sequencing is a powerful method for diagnosing syndromic growth disorders. It enables us to understand molecular pathophysiology and investigate new treatments for growth disorders.

Growth hormone and early treatment.

Growth hormone (GH) treatment is approved by the US Food and Drug Administration (FDA) not only for GH deficiency (GHD) but also for other childhood growth disorders with growth failure and/or short stature. GHD is the most frequent endocrine disorder presenting with short stature in childhood. During neonatal period, metabolic effects due to congenital GHD require a prompt replacement therapy to avoid possible life-threatening complications. In childhood and adolescence, growth impairment is the most evident effect of GHD and early treatment has the aim of restore normal growth and to reach normal adult height. We reassume in this review the conditions causing GHD and the diagnostic challenge to reach an early diagnosis, and an early treatment, necessary to obtain the best results. Finally, we summarize results obtained in clinical studies about pediatric patients with GHD treated at an early age, in which a marked early catch-up growth and a normalization of adult height were obtained.

CANT1 mutation is also responsible for Desbuquois dysplasia, type 2 and Kim variant.

BACKGROUND: Desbuquois dysplasia (DD) is a recessively inherited condition characterised by short stature, generalised skeletal dysplasia and advanced bone maturation. DD is both clinically and radiographically heterogeneous, and two subtypes have been distinguished based on the presence (type 1) or absence (type 2) of an accessory metacarpal bone. In addition, an apparently distinct variant without additional metacarpal bone but with short metacarpals and long phalanges (Kim variant) has been described recently. Mutations in the gene that encodes for CANT1 (calcium-activated nucleotidase 1) have been identified in a subset of patients with DD type 1. METHODS: A series of 11 subjects with DD from eight families (one type 1, two type 2, five Kim variant) were examined for CANT1 mutations by direct sequencing of all coding exons and their flanking introns. RESULTS: Eight distinct mutations were identified in seven families (one type 1, one type 2 and all 5 Kim variant): three were nonsense and five were missense. All missense mutations occurred at highly conserved amino acids in the nucleotidase conserved regions of CANT1. Measurement of nucleotidase activity in vitro showed that the missense mutations were all associated with loss-of-function. CONCLUSION: The clinical-radiographic spectrum produced by CANT1 mutations must be extended to include DD type 2 and Kim variant. While presence or absence of an additional metacarpal ossification centre has been used to distinguish subtypes of DD, this sign is not a distinctive criterion to predict the molecular basis in DD.

Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia.

BACKGROUND: In total, 43 patients having short stature syndrome in 37 Yakut families with autosomal recessive prenatal and postnatal nonprogressive growth failure and facial dysmorphism but with normal intelligence have been identified. METHODS: Because Yakuts are considered as a population isolate and the disease is rare in other populations, genomewide homozygosity mapping was performed using 763 microsatellite markers and candidate gene approach in the critical region to identify the causative gene for the short stature syndrome in Yakut. RESULTS: All families shared an identical haplotype in the same region as the identical loci responsible for 3-M and gloomy face syndromes and a novel homozygous 4582insT mutation in Cullin 7 (CUL7) was found, which resulted in a frameshift mutation and the formation of a subsequent premature stop codon at 1553 (Q1553X). Yakut patients with short stature syndrome have unique features such as a high frequency of neonatal respiratory distress and few bone abnormalities, whereas the clinical features of the other Yakut patients were similar to those of 3-M syndrome. Furthermore, abnormal vascularisation was present in the fetal placenta and an abnormal development of cartilage tissue in the bronchus of a fetus with CUL7 mutation. CONCLUSION: These findings may provide a new understanding of the clinical diversity and pathogenesis of short stature syndrome with CUL7 mutation.

15N tracer techniques for the differential diagnosis of dwarfism and prediction of growth hormone action in children.

[15N]Glycine in a single oral dose was used to study nitrogen turnover in 18 short children, aged 3-14 yr. On the basis of their serum GH responses to insulin-induced hypoglycemia, the patients were divided into 3 groups: complete GH deficiency (GHD; n = 5); partial GH deficiency (pGHD; n = 6), and children with constitutional growth delay and familial short stature (CGD/FSS; n = 7). The mean 48-h renal excretion of 15N by patients with GHD was 66.09 +/- 14.12% (+/- SD) of the tracer dose. This decreased to 27.64 +/- 5.33% after two injections of 10 IU/m2 GH (P less than 0.001). 15N excretion by patients with pGHD was 47.19 +/- 13.42%, and it decreased after GH injection to 22.69 +/- 4.58% (P less than 0.005). Patients with CGD/FSS had 15N excretion of 37.27 +/- 5.68%, and it did not change in response to GH. The mean protein synthesis rate in GHD patients was extremely low, and it increased after GH injection from 0.99 +/- 0.46 to 3.53 +/- 0.43 g/kg X day. In pGHD patients the protein synthesis rate increased from 2.62 +/- 0.84 to 4.50 +/- 1.09 g/kg X day. The CGD/FSS patients had no change in protein synthesis rate after GH. Our results suggest that studies of the metabolism of [15N]glycine might be of value in predicting responsiveness to GH therapy.

Osteodysplastic primordial dwarfism: report of a further patient with manifestations similar to those seen in patients with types I and III.

We describe a female infant with low birthweight osteodysplastic microcephalic dwarfism. The child has many manifestations in common with those seen in osteodysplastic primordial dwarfism types I and III. The classification of this heterogeneous group of disorders is discussed in the light of the above case.

Microdontia with severe microcephaly and short stature in two brothers: osteodysplastic primordial dwarfism with dental findings.

Two brothers from a black family had microcephaly, short stature, and generalized microdontia. Endocrine and chromosome studies were normal, and mild skeletal manifestations were present. The patients may represent a distinct dental-skeletal dysplasia, possibly osteodysplastic primordial dwarfism type II. Attention to dental manifestations in similar cases may be useful for classification.

Achondrogenesis: a review with special consideration of achondrogenesis type II (Langer-Saldino).

We describe two dwarfed infants with large head, short neck and chest, prominent abdomen, and short limbs. Both died neonatally. Radiographic and morphologic characteristics identified the Langer-Saldino form of achondrogenesis (type II). Review of type II achondrogenesis documented distinctive clinical and anthropometric manifestations (fewer stillbirths, longer survival time and gestation period, larger size of the baby, longer limbs, and characteristic craniofacial features) as compared with type I achondrogenesis (Parenti-Fraccaro).

Dyssegmental dysplasias: clinical, radiographic, and morphologic evidence of heterogeneity.

The dyssegmental dysplasias are lethal forms of neonatal short-limbed dwarfism in which vertebral segmentation defects and short, thick, bowed long bones are the prominent radiographic features. Clinically, unusual facies, short neck, narrow thorax, cleft palate, and reduced joint mobility are commonly seen. To date, 18 cases of dyssegmental dysplasia have been reported. Reports of three pairs of affected sibs suggest autosomal recessive inheritance. We have studied eight additional cases of dyssegmental dysplasia, including one pair of affected sibs. Clinical, radiographic, and histologic examination of these new cases and review of the literature demonstrates the presence of at least two distinct forms of dyssegmental dysplasia. The milder form, "dyssegmental dysplasia, type Rolland-Desbuquois," is characterized clinically by frequent survival beyond the newborn period and by distinct radiographic changes resembling Kniest dysplasia. The severe form, "dyssegmental dysplasia, type Silverman-Handmarker," is characterized by stillbirth or death within the first few days of life and by distinct and more severe radiographic changes. In addition, we have demonstrated chondro-osseous morphologic differences between the two disorders by light and electron microscopy. We conclude that there are at least two forms of dyssegmental dysplasia, each autosomal recessive, which can be delineated on clinical, radiographic and morphologic grounds.

Spondylocostal/spondylothoracic dysostosis: the clinical basis for prognosticating and genetic counseling.

Short trunk dwarfism involving skeletal anomalies of vertebrae and ribs have been reported under various names. Both dominant and recessive and severe and mild conditions are found. We report on a patient without a severe handicap by age 3 years despite severe involvement of the thorax at birth, suggesting that a more complete classification of such anomalies is needed for counseling. We have used an objective method to classify 39 informative patients from the literature, 35 said to have a recessive disease and four a dominant one. Two patients with the costovertebral segmentation defect with mesomelia (COVESDEM) syndrome were added for comparison with our patient. The results of cluster analysis show that there are three phenotypic groups of patients. Cluster 1 contains 19 patients with a severe form of spondylothoracic dysplasia; cluster 2 includes patients with a mild autosomal recessive and a dominant type; cluster 3 groups the two sibs with the COVESDEM syndrome and our patient. One must be cautious in advising families of the prognosis for a child with severe structural chest deformity since it may not be severe from a functional point of view. More data are needed for complete discrimination between the mild autosomal recessive and dominant forms.

Multiple vertebral segmentation defects: analysis of 26 new patients and review of the literature.

To further delineate and classify those forms of short trunk dwarfism characterized by multiple vertebral segmentation defects, we analyzed 26 new patients and reviewed 115 described in the literature. Three distinct entities were recognized based on radiographic and clinical findings. Jarcho-Levin syndrome is the lethal autosomal recessive form, characterized by a symmetric crab-like chest. Spondylocostal dysostosis is the benign autosomal dominant condition. Spondylothoracic dysostosis shows considerable clinical and radiographic overlap with spondylocostal dysostosis. Malformations observed in association with multiple vertebral segmentation defects are more common in the sporadic patients. Analysis of the 26 new individuals revealed that the body segment in which these nonvertebral malformations occur corresponds to the site of the vertebral segmentation defects.

Do some patients with Seckel syndrome have hematological problems and/or chromosome breakage?

We report on a 12-yr-old female and a 14-yr-old male with Seckel syndrome. The 12-yr-old female had pancytopenia, which is seen occasionally in patients with Seckel syndrome and is also a feature of Fanconi anemia, a well-recognized autosomal recessive dwarfism syndrome with chromosome instability. Chromosome breakage analysis of both of our patients also indicated chromosome instability. We suggest that there may be a subgroup of Seckel syndrome patients with chromosome instability and/or hematological problems.

Autopsy case of microcephalic osteodysplastic primordial "dwarfism" type II.

Microcephalic osteodysplastic primordial "dwarfism" (MOPD) is a group of disorders similar to Seckel syndrome. Three subtypes (types I-III) have been reported. We report here the first autopsy case of MOPD type II. The patient was a Japanese girl with typical clinical and radiological manifestations of MOPD type II. The manifestations included severe intrauterine and postnatal growth failure, microcephaly, a distinctive facial appearance, micromelia, brachytelephalangy, coxa vara, and V-shaped metaphyses of the distal femora. Other than small cerebral hemispheres, no neuropathological abnormalities were found. Chondro-osseous histology showed thinning of the growth plate, ballooned chondrocytes, reduced cellularity, lack of zonal and columnar formations, and poor formation of primary trabeculae. These findings suggest that impairment of chondrocytic formation and differentiation is the major pathogenesis of MOPD type II.

Osteodysplastic primordial dwarfism: report of a further case with manifestations similar to those of types I and III.

We describe a male infant with microcephalic osteodysplastic primordial dwarfism. The clinical and radiological manifestations most closely resemble those of the patient described by Winter et al. to have manifestations overlapping with both osteodysplastic primordial dwarfism types I and III. The classification of the patient within the spectrum of osteodysplastic primordial dwarfism is discussed and the distinctive neuropathology documented.

Studies of microcephalic primordial dwarfism II: the osteodysplastic type II of primordial dwarfism.

We describe three unrelated patients with intrauterine growth retardation (IUGR) and nearly identical bone changes. In certain respects, they share similarities with the Seckel syndrome: small forehead, moderately prominent nose, micrognathia, pronounced intrauterine and postnatal growth retardation, microcephaly, and mental retardation. Differences from the Seckel syndrome include disproportionate shortness of forearms and legs in the first years of life, brachymesophalangy, brachymetacarpy I, V-shaped flare of at least the distal femoral metaphyses, triangular shape of the distal femoral epiphyses, a high and narrow pelvis, proximal femoral epiphysiolysis, and coxa vara. Hormone studies in two cases demonstrated no gross disturbances, especially no deficit of hGH and somatomedin. Two previously reported cases referred to as Seckel syndrome had nearly identical bone changes. The cause of this "new" type of IUGR remains unclear.

Osteodysplastic primordial dwarfism: a case with features of type II.

We describe a 22-month-old Japanese girl with severe microcephaly with a prominent nose and a receding chin, developmental delay, marked intrauterine and postnatal dwarfism with limb shortening and brachydactyly, and distinctive radiological changes of the skeleton. The radiological findings include hypoplasia of the short tubular bones, multiple pseudoepiphyses in the bases of the metacarpals, coxa valga, a wide pelvis with iliac flaring, thoracolumbar scoliosis, and disharmonious ossification delay. The clinical and radiological features are somewhat different from those of previously reported cases with osteodysplastic primordial dwarfism. The clinical and radiological manifestations of osteodysplastic primordial dwarfism are reviewed and compared with those in our patient.

[Bird headed dwarfism in Seckel syndrome. Nosologic difficulties]. / Le nanisme à tête d'oiseau ou syndrome de Seckel. Difficultés nosologiques.

Seckel syndrome is a clinical picture which associates four main features: intrauterine growth retardation, microcephaly often due to craniosynostosis, orofacial dysmorphology with bird headed appearance and variable mental retardation which is present after several months. Malformations of the central nervous system, limbs, and hair, may also be observed. On the basis of 78 cases reported in the literature, the authors discuss the validity of the morphological features of the syndrome. It is likely that the variability in the expressivity of each symptom explains its heterogeneity. According to the radiological abnormalities, three different forms of the syndrome have been described. Seckel syndrome is a genetic disorder with autosomal recessive inheritance. Its ethiopatogeny remains unclear. Hopefully linkage studies will allow to map the gene in order to determine the underlying abnormal protein.

[Campomelic dwarfism. Its placement in the heterogeneous group of congenital bowing of the limbs]. / Il nanismo campomelico. Sua collocazione nel gruppo eterogeneo degli incurvamenti congeniti degli arti.

The campomelic (camptomelic) dwarfism is a rare congenital syndrome which includes, in addition to typical angulations of femora and tibiae (campomelia or camptomelia = bowed or bent limbs), other skeletal abnormalities and visceral lesions, particularly of the brain and of the respiratory tract, which are almost always responsible of early death. Congenital bowing of limbs are seen in various conditions: as isolated deformity (or component of a strictly localised deformity); as integrating part of a more extensive syndrome (the campomelic dwarfism falls within this subgroup); as secondary element of complex syndromes, such as the severe congenital demineralizations of the skeleton. The differential diagnosis must take into account this various conditions, together with other congenital dwarfisms, particularly those incompatible with life (see table 1 e 2). A typical case of campomelic dwarfism is presented.