Dynamic analysis of amplitude of low-frequency fluctuation in children with growth hormone deficiency.

OBJECTIVE: Growth hormone (GH) affects brain activities and promotes growth and development. GH is a peptide hormone secreted by the anterior pituitary gland and is tied to behavior and cognitive function. Growth hormone deficiency (GHD) is the most common type of pathological short stature in children. Existing studies provide evidence that GHD may impact functional brain activities. The aim of this study was to investigate dynamic local brain activity in GHD children. METHOD: In this study, we combined amplitude of low-frequency fluctuations (ALFF) and sliding-window techniques to examine the local brain activity of children with GHD. The resting-state functional magnetic resonance imaging (fMRI) data were collected from 26 children with GHD and 15 age- and sex-matched healthy controls (HC). RESULT: Our results showed significant abnormal temporal variability of dynamic ALFF in widespread regions in children with GHD, primarily in the frontal gyrus, temporal gyrus, and parietal lobule. CONCLUSION: The dALFF can capture dynamic changes in brain spontaneous activity, which are related to behavior and cognition. Based on this dynamic local brain activity, the results of this study provide a better understanding of the pathophysiological mechanism in children with GHD.

Growth and Growth Hormone through the Ages: Art and Science.

BACKGROUND: People have long been fascinated with the size and growth of living things, from the giants of classic mythology and art to the little people who also have appeared in classical art, as well as the courts of European monarchs, and were exploited in "shows." Serious medical evaluation began in the late 19th century with the description of acromegaly and its association with pituitary tumors. In the early 20th century, multiple investigators attempted to extract a growth-promoting factor from the anterior pituitary and then, over the decades, to purify it and distinguish it from other anterior pituitary hormones. With relatively pure growth hormone (GH), its biological activity in growth promotion and as a metabolic hormone were studied, and species specificity became apparent: primate GH was the only GH active in man. Human GH was prepared from cadaveric pituitaries and distributed by the NIH to treat children with GH deficiency, but there was never enough pituitary hGH for all of the children who required it. When Creutzfeldt-Jakob disease was found in some patients who received pituitary GH, the production and FDA approval of biosynthetic hGH dramatically accelerated. With a large supply, one could treat those who were GH deficient and test its efficacy in other causes of short stature; longer acting versions of hGH have now been developed, tested, and in a few instances received FDA approval. SUMMARY: It has been a long journey from the description of over- and underproduction of GH in animals to the production and clinical use of the biosynthetic hormones. KEY MESSAGES: The efforts of basic scientists led to the extraction and purification of GH. Clinical scientists have expanded the appropriate use of hGH for short children with conditions in addition to GH deficiency.

Palaeohistology reveals a slow pace of life for the dwarfed Sicilian elephant.

The 1-m-tall dwarf elephant Palaeoloxodon falconeri from the Pleistocene of Sicily (Italy) is an extreme example of insular dwarfism and epitomizes the Island Rule. Based on scaling of life-history (LH) traits with body mass, P. falconeri is widely considered to be 'r-selected' by truncation of the growth period, associated with an early onset of reproduction and an abbreviated lifespan. These conjectures are, however, at odds with predictions from LH models for adaptive shifts in body size on islands. To settle the LH strategy of P. falconeri, we used bone, molar, and tusk histology to infer growth rates, age at first reproduction, and longevity. Our results from all approaches are congruent and provide evidence that the insular dwarf elephant grew at very slow rates over an extended period; attained maturity at the age of 15 years; and had a minimum lifespan of 68 years. This surpasses not only the values predicted from body mass but even those of both its giant sister taxon (P. antiquus) and its large mainland cousin (L. africana). The suite of LH traits of P. falconeri is consistent with the LH data hitherto inferred for other dwarfed insular mammals. P. falconeri, thus, not only epitomizes the Island Rule but it can also be viewed as a paradigm of evolutionary change towards a slow LH that accompanies the process of dwarfing in insular mammals.

Wide Fontanels, Delayed Speech Development and Hoarse Voice as Useful Signs in the Diagnosis of KBG Syndrome: A Clinical Description of 23 Cases with Pathogenic Variants Involving the ANKRD11 Gene or Submicroscopic Chromosomal Rearrangements of 16q24.3.

KBG syndrome is a neurodevelopmental autosomal dominant disorder characterized by short stature, macrodontia, developmental delay, behavioral problems, speech delay and delayed closing of fontanels. Most patients with KBG syndrome are found to have a mutation in the ANKRD11 gene or a chromosomal rearrangement involving this gene. We hereby present clinical evaluations of 23 patients aged 4 months to 26 years manifesting clinical features of KBG syndrome. Mutation analysis in the patients was performed using panel or exome sequencing and array CGH. Besides possessing dysmorphic features typical of the KBG syndrome, nearly all patients had psychomotor hyperactivity (86%), 81% had delayed speech, 61% had poor weight gain, 56% had delayed closure of fontanel and 56% had a hoarse voice. Macrodontia and a height range of -1 SDs to -2 SDs were noted in about half of the patients; only two patients presented with short stature below -3 SDs. The fact that wide, delayed closing fontanels were observed in more than half of our patients with KBG syndrome confirms the role of the ANKRD11 gene in skull formation and suture fusion. This clinical feature could be key to the diagnosis of KBG syndrome, especially in young children. Hoarse voice is a previously undescribed phenotype of KBG syndrome and could further reinforce clinical diagnosis.

Oliver McFarlane syndrome: two new cases and a review of the literature.

BACKGROUND: Oliver McFarlane syndrome is a rare syndrome. Clinical presentations include trichomegaly, chorioretinal degeneration, pituitary hormone deficits, and neurological manifestations. Genetic analysis has recently placed this syndrome within the group of PNPLA6-related disorders. Here, we describe two new individuals and review the previously published cases. MATERIALS AND METHODS: Clinical investigations were carried out in accordance with local guidelines and clinical information was retrieved from medical records. Genetic studies were carried out using next-generation sequencing based clinical exome sequencing. A PubMed literature search was performed with a review of the published clinical cases of Oliver McFarlane syndrome. RESULTS: Our first individual was a 36-year-old woman with 32 years of follow up and our second individual was a 3-year-old boy. Both individuals were born preterm and presented with prolonged neonatal respiratory distress, trichomegaly, early growth retardation, retinopathy and sparse depigmented hair. So far, none of our cases have demonstrated cognitive impairment or progressive neurological symptoms, but the child revealed persistent abnormal lung structure. Both individuals were compound heterozygous for pathogenic PNPLA6 variants, one of which was novel. We found other 31 clinically documented published cases. CONCLUSIONS: Our two new unrelated cases of Oliver McFarlane Syndrome demonstrate early ophthalmological and systemic findings of this rare syndrome and the progressive nature of the retinopathy with a long follow-up. PNPLA6-related disorders are a phenotypically highly heterogenous group where alterations in the phosphatidylcholine metabolism can lead to manifestations in different tissues with no clear genotype-phenotype correlation.

Dmrt2 promotes transition of endochondral bone formation by linking Sox9 and Runx2.

Endochondral bone formation is fundamental for skeletal development. During this process, chondrocytes undergo multiple steps of differentiation and coordinated transition from a proliferating to a hypertrophic stage, which is critical to advance skeletal development. Here, we identified the transcription factor Dmrt2 (double-sex and mab-3 related transcription factor 2) as a Sox9-inducible gene that promotes chondrocyte hypertrophy in pre-hypertrophic chondrocytes. Epigenetic analysis further demonstrated that Sox9 regulates Dmrt2 expression through an active enhancer located 18 kb upstream of the Dmrt2 gene and that this enhancer's chromatin status is progressively activated through chondrocyte differentiation. Dmrt2-knockout mice exhibited a dwarf phenotype with delayed initiation of chondrocyte hypertrophy. Dmrt2 augmented hypertrophic chondrocyte gene expression including Ihh through physical and functional interaction with Runx2. Furthermore, Dmrt2 deficiency reduced Runx2-dependent Ihh expression. Our findings suggest that Dmrt2 is critical for sequential chondrocyte differentiation during endochondral bone formation and coordinates the transcriptional network between Sox9 and Runx2.

Craniofacial phenotypes associated with Robinow syndrome.

Robinow syndrome is characterized by mesomelic limb shortening, hemivertebrae, and genital hypoplasia. Due to low prevalence and considerable phenotypic variability, it has been challenging to definitively characterize features of Robinow syndrome. While craniofacial abnormalities associated with Robinow syndrome have been broadly described, there is a lack of detailed descriptions of genotype-specific phenotypic craniofacial features. Patients with Robinow syndrome were invited for a multidisciplinary evaluation conducted by specialist physicians at our institution. A focused assessment of the craniofacial manifestations was performed by a single expert examiner using clinical examination and standard photographic images. A total of 13 patients with clinical and molecular diagnoses consistent with either dominant Robinow syndrome (DRS) or recessive Robinow syndrome (RRS) were evaluated. On craniofacial examination, gingival hyperplasia was nearly ubiquitous in all patients. Orbital hypertelorism, a short nose with anteverted and flared nares, a triangular mouth with a long philtrum, cleft palate, macrocephaly, and frontal bossing were not observed in all individuals but affected individuals with both DRS and RRS. Other anomalies were more selective in their distribution in this patient cohort. We present a comprehensive analysis of the craniofacial findings in patients with Robinow Syndrome, describing associated morphological features and correlating phenotypic manifestations to underlying genotype in a manner relevant for early recognition and focused evaluation of these patients.

Immunodeficiency in a patient with microcephalic osteodysplastic primordial dwarfism type I as compared to Roifman syndrome.

BACKGROUND: Microcephalic osteodysplastic primordial dwarfism type I (MOPD I, also known as Taybi-Linder syndrome) is a rare genetic disorder associated with severe intrauterine growth retardation, short stature, microcephaly, brain anomalies, stunted limbs, and early mortality. RNU4ATAC, the gene responsible for this disorder, does not encode a protein but instead the U4atac small nuclear RNA (snRNA), a crucial component of the minor spliceosome. Roifman syndrome is an allelic disorder of MOPD I that is characterized by immunodeficiency complications. CASE REPORT: The patient described herein is an 18-year-old woman exhibiting congenital dwarfism and microcephaly with structural brain anomaly. She suffered human herpesvirus 6 (HHV-6)-associated acute necrotizing encephalopathy at the age of one, thereafter resulting in severe psychomotor disabilities. Genetic analysis using gene microarray and whole-exome sequencing could not identify the cause of her congenital anomalies. However, Sanger sequencing revealed a compound heterozygous mutation within RNU4ATAC (NR_023343.1:n.[50G > A];[55G > A]). Immunological findings showed decreases in total lymphocytes, CD4+ T cells, and T cell regenerative activity. Furthermore, antibodies against varicella-zoster, rubella, measles, mumps, and influenza were very low or negative despite having received vaccinations for these viruses. HHV-6 IgG antibodies were also undetected. DISCUSSION: The patient here exhibited a marked MOPD I phenotype complicated by various immunodeficiencies. Previous studies have not demonstrated immunodeficiency comorbidities within MOPD I subjects, but this report suggests an evident immunodeficiency in MOPD I. Patients with MOPD I should be treated with one of the immunodeficiency syndromes.

Novel pathogenic genomic variants leading to autosomal dominant and recessive Robinow syndrome.

Robinow syndrome (RS) is a genetically heterogeneous disorder characterized by skeletal dysplasia and a distinctive facial appearance. Previous studies have revealed locus heterogeneity with rare variants in DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A underlying the etiology of RS. The aforementioned "Robinow-associated genes" and their gene products all play a role in the WNT/planar cell polarity signaling pathway. We performed gene-targeted Sanger sequencing, exome sequencing, genome sequencing, and array comparative genomic hybridization on four subjects with a clinical diagnosis of RS who had not had prior DNA testing. Individuals in our cohort were found to carry pathogenic or likely pathogenic variants in three RS related genes: DVL1, ROR2, and NXN. One subject was found to have a nonsense variant (c.817C > T [p.Gln273*]) in NXN in trans with an ~1 Mb telomeric deletion on chromosome 17p containing NXN, which supports our contention that biallelic NXN variant alleles are responsible for a novel autosomal recessive RS locus. These findings provide increased understanding of the role of WNT signaling in skeletal development and maintenance. These data further support the hypothesis that dysregulation of the noncanonical WNT pathway in humans gives rise to RS.

Neurocognitive, adaptive, and psychosocial functioning in individuals with Robinow syndrome.

It has been estimated that 10-15% of people with Robinow syndrome (RS) show delayed development, but no studies have formally assessed developmental domains. The objective of this study is to provide the first description of cognitive, adaptive, and psychological functioning in RS. Thirteen participants (10 males) aged 4-51 years were seen for neuropsychological screening. Eight had autosomal-dominant RS (DVL1, n = 5; WNT5A, n = 3), four had autosomal-recessive RS (NXN, n = 2; ROR2, n = 2), and one had a mutation on an RS candidate gene (GPC4). Participants completed measures of intellectual, fine-motor, adaptive, executive, and psychological functioning. Findings indicated generally average intellectual functioning and low-average visuomotor skills. Adaptive functioning was average in autosomal-recessive RS (RRS) but low average in autosomal-dominant RS (DRS). Parent-report indicated executive dysfunction and attention problems in 4/8 children, 3/4 of whom had a DVL1 variant; adult self-report did not indicate similar difficulties. Learning disabilities were also reported in 4/8 individuals with DRS, 3/4 of whom had a DVL1 variant. Peer problems were reported for a majority of participants, many of whom also reported emotional concerns. Altogether, the findings indicate average neurocognitive functioning in RRS. In contrast, DRS, especially DVL1 pathogenic alleles, may confer specific risk for neurodevelopmental disability.

Extremity anomalies associated with Robinow syndrome.

Robinow syndrome, a rare genetic disorder, is characterized by skeletal dysplasia with, among other anomalies, extremity and hand anomalies. There is locus heterogeneity and both dominant and recessive inheritance. A detailed description of associated extremity and hand anomalies does not currently exist due to the rarity of this syndrome. This study seeks to document the hand anomalies present in Robinow syndrome to allow for improved rates of timely and accurate diagnosis. A focused assessment of the extremities and stature was performed using clinical examination and standard photographic images. A total of 13 patients with clinical and molecular diagnosis consistent with dominant Robinow syndrome or recessive Robinow syndrome were evaluated. All patients had limb shortening, the most common of which was mesomelia; however, rhizomelia and micromelia were also seen. These findings are relevant to clinical characterization, particularly as Robinow syndrome has classically been defined as a "mesomelic disorder." A total of eight distinct hand anomalies were identified in 12 patients with both autosomal recessive and dominant forms of Robinow syndrome. One patient did not present with any hand differences. The most common hand findings included brachydactyly, broad thumbs, and clinodactyly. A thorough understanding of the breadth of Robinow syndrome-associated extremity and hand anomalies can aid in early patient identification, improving rates of timely diagnosis and allowing for proactive management of sequelae.

Adult Chinese twins with Kenny-Caffey syndrome type 2: A potential age-dependent phenotype and review of literature.

Kenny-Caffey syndrome (KCS) type 2 (OMIM 127000) is a rare syndromic cause of hypoparathyroidism which is characterized by proportionate short stature, long bone abnormalities, delayed closure of anterior fontanelle, eye abnormalities, and normal intelligence. It is caused by variants in FAM111A (NM_001942519.1). In this review, we reported the first Chinese patients, a pair of monozygotic twins, with genetically confirmed KCS type 2 with over 20 years follow-up. We summarized the clinical features of 14 previously reported and genetically confirmed KCS type 2 patients; our twin patients exhibited a unique spinal manifestation which could be an important age-dependent feature of KCS type 2. In this review, over 60% KCS type 2 patients had dental problem and over 80% suffered from refractive errors or structural eye abnormalities. Therefore, early dental, ophthalmological, and orthopedic assessments are warranted for KCS type 2 patients. Micro-orchidism, previously reported in KCS type 2 patients, was also detected in our patients. The possibility of subfertility should be considered in male KCS type 2 patients. A multidisciplinary management approach for this rare syndrome is recommended.

Robinow syndrome: Genital analysis, genetic heterogeneity, and associated psychological impact.

Robinow syndrome (RS) is a rare, pleiotropic genetic disorder. While it has been reported that males with Robinow syndrome may have genitourinary atypicalities, these have not been systematically studied. We hypothesized that the underlying gene involved plays a role in the clinical variability of associated genital findings and that the phenotypic appearance of the genitalia in RS may have a psychological impact. Urologic-specific examination consisted of detailed examination and a questionnaire to investigate the psychological impact of the genital phenotype. Nine males agreed to a full evaluation. Average age was 19.9 years, penile length was 32.5 mm, stretched length 53 mm, and width 24.4 mm. Penile transposition occurred in all 9 male who allowed full examination. Undescended testicles were noted in 4/10, testicular atrophy in 5/9, buried penis in 7/9, hypospadias in 5/8, and a large penopubic gap (space between dorsum of penis base and pubic bone) in 5/6. In this cohort, 78% answered our semi-quantitative pilot questionnaire that identified diminished sexuality, sexual function, and self-perception. In conclusion, RS has unique, hallmark genital findings including penile transposition, buried penis, undescended testes, and large penopubic gaps. Genital phenotype in males was not shown to correlate with the specific gene involved for each patient. Surgical approaches and other interventions should be studied to address the findings of decreased sexuality and self-perception. It is the authors' opinion that intervention to provide the appearance of penile lengthening be postponed until puberty to allow for maximal natural phallic growth.

Further defining the clinical and molecular spectrum of acromesomelic dysplasia type maroteaux: a Turkish tertiary center experience.

Acromesomelic dysplasia type Maroteaux (AMDM, OMIM #602875) is an autosomal recessive disorder characterized by severe short stature, shortened middle and distal segments of the limbs, redundant skin of fingers, radial head subluxation or dislocation, large great toes and cranium, and normal intelligence. Only the skeletal system appears to be consistently affected. AMDM is caused by biallelic loss-of-function variants in the natriuretic peptide receptor B (NPRB or NPR2, OMIM #108961) which is involved in endochondral ossification and longitudinal growth of limbs and vertebrae. In this study, we investigated 26 AMDM patients from 22 unrelated families and revealed their genetic etiology in 20 families, via Sanger sequencing or exome sequencing. A total of 22 distinct variants in NPR2 (14 missense, 5 nonsense, 2 intronic, and 1 one-amino acid deletion) were detected, among which 15 were novel. They were in homozygous states in 19 patients and in compound heterozygous states in four patients. Parents with heterozygous NPR2 variants were significantly shorter than the control. Extra-skeletal abnormalities, including global developmental delay/intellectual disability, nephrolithiasis, renal cyst, and oligodontia were noted in the patient cohort. The high parental consanguinity rate might have contributed to these findings, probably associated with other gene variants. This study represents the largest cohort of AMDM from Turkey and regional countries and further expands the molecular and clinical spectrum of AMDM.

Screening for imprinting disorders in 58 patients with clinically diagnosed idiopathic short stature.

Objectives Imprinted genes have important roles for normal growth and development. Imprinting disorders (IDs) such as Silver-Russell syndrome and Temple syndrome are rare diseases that typically cause short children born small for gestational age (SGA). However, some patients with short stature (SS) caused by IDs were born non-SGA. To date, the contribution of IDs to idiopathic short stature (ISS) has been poorly investigated. The aim of this study was to clarify the contribution of IDs to ISS. Methods We conducted methylation analysis for 10 differentially methylated regions using pyrosequencing to detect known IDs in 58 patients (31 male and 27 female children, height standard deviation score -4.2 to -2.0) carrying a clinical diagnosis of ISS. Results We identified no patient with IDs among these patients with ISS. Conclusions These results indicate that IDs are rare in patients having ISS, and that imprinted genes affect fetal growth more than postnatal growth. Because patients with IDs born non-SGA usually have clinical features characteristic of each ID, in addition to SS, the patients with ISS as a clinical diagnosis may not be associated with IDs. It is unlikely that cases clinically diagnosed with ISS are caused by IDs leading to growth failure.

Aarskog-Scott syndrome: clinical and molecular characterisation of a family with the coexistence of a novel FGD1 mutation and 16p13.11-p12.3 microduplication.

Aarskog-Scott syndrome (AAS), also known as facio-genital dysplasia or faciodigitogenital syndrome, is a rare genetic disorder clinically characterised by facial, limb and genitalanomalies. Although also autosomal dominance and recessive patterns have been reported, up to now, only an X linked form associated to mutations of the FGD1 gene has been recognised as causative for this syndrome.In this case report, we describe a large Italian family in which three members across three generations show classical features of the syndrome. The youngest patient, the proband, and his mother were both molecularly studied and characterised for the not previously reported variant c.1828C>T (p. Arg610*) in the FGD1 gene but with the classic phenotype of AAS. Additionally, both the proband and his mother present a 2.5 Mb 16p13.11-p12.3 microduplication, a genetic variant still unclear for the phenotypic consequences: the co-occurrence of the two rare conditions is discussed for the possible clinical significance.

Detection of SHOX Gene Variations in Patients with Skeletal Abnormalities with or without Short Stature

Objective: SHOX gene mutations constitute one of the genetic causes of short stature. The clinical phenotype includes variable degrees of growth impairment, such as Langer mesomelic dysplasia (LMD), Léri-Weill dyschondrosteosis (LWD) or idiopathic short stature (ISS). The aim of this study was to describe the clinical features and molecular results of SHOX deficiency in a group of Turkish patients who had skeletal findings with and without short stature. Methods: Forty-six patients with ISS, disproportionate short stature or skeletal findings without short stature from 35 different families were included. SHOX gene analysis was performed using Sanger sequencing and multiplex ligation-dependent probe amplification analysis. Results: Three different point mutations (two nonsense, one frameshift) and one whole SHOX gene deletion were detected in 15 patients from four different families. While 4/15 patients had LMD, the remaining patients had clinical features compatible with LWD. Madelung's deformity, cubitus valgus, muscular hypertrophy and short forearm were the most common phenotypic features, as well as short stature. Additionally, hearing loss was detected in two patients with LMD. Conclusion: This study has presented the clinical spectrum and molecular findings of 15 patients with SHOX gene mutations or deletions. SHOX deficiency should be especially considered in patients who have disproportionate short stature or forearm anomalies with or without short stature. Although most of the patients had partial or whole gene deletions, SHOX gene sequencing should be performed in suspected cases. Furthermore, conductive hearing loss may rarely accompany these clinical manifestations.

Biallelic variants in SLC35C1 as a cause of isolated short stature with intellectual disability.

Variants in SLC35C1 underlie leucocyte adhesion deficiency (LADII) or congenital disorder of glycosylation type 2c (CDGIIc), an autosomal recessive disorder of fucosylation. This immunodeficiency syndrome is generally characterized by severe recurrent infections, Bombay blood group, reduced growth and intellectual disability (ID). Features are all caused by an inability to generate key fucosylated molecules due to a defective transport of GDP-fucose into the Golgi. Here we report the use of exome sequencing to identify biallelic variants in SLC35C1 (c.501_503delCTT, p.(Phe168del) and c.891T > G, p.(Asn297Lys)) in an individual with short stature and ID. Retrospective clinical examination based on the genetic findings revealed increased otitis media as the only immunological feature present in this child. Biochemical analysis of patient serum identified a clear but mild decrease in protein fucosylation. Modelling all described missense mutations on a SLC35C1 protein model showed pathogenic substitutions localise to close to the dimer interface, providing insight into the possible pathophysiology of non-synonymous causative variants identified in patients. Our evidence confirms this is the second family presenting with only a subset of features and broadens the clinical presentation of this syndrome. Of note, both families segregated a common allele (p.Phe168del), suggesting there could be an associated genotype-phenotype relationship for specific variants. Based on two out of 14 reported families not presenting with the characteristic features of SLC35C1-CDG, we suggest there is clinical utility in considering this gene in patients with short stature and ID.

Probing Pedomorphy and Prolonged Lifespan in Naked Mole-Rats and Dwarf Mice.

Pedomorphy, maintenance of juvenile traits throughout life, is most pronounced in extraordinarily long-lived naked mole-rats. Many of these traits (e.g., slow growth rates, low hormone levels, and delayed sexual maturity) are shared with spontaneously mutated, long-lived dwarf mice. Although some youthful traits likely evolved as adaptations to subterranean habitats (e.g., thermolability), the nature of these intrinsic pedomorphic features may also contribute to their prolonged youthfulness, longevity, and healthspan.

Increasing knowledge in IGF1R defects: lessons from 35 new patients.

BACKGROUND: The type 1 insulin-like growth factor receptor (IGF1R) is a keystone of fetal growth regulation by mediating the effects of IGF-I and IGF-II. Recently, a cohort of patients carrying an IGF1R defect was described, from which a clinical score was established for diagnosis. We assessed this score in a large cohort of patients with identified IGF1R defects, as no external validation was available. Furthermore, we aimed to develop a functional test to allow the classification of variants of unknown significance (VUS) in vitro. METHODS: DNA was tested for either deletions or single nucleotide variant (SNV) and the phosphorylation of downstream pathways studied after stimulation with IGF-I by western blot analysis of fibroblast of nine patients. RESULTS: We detected 21 IGF1R defects in 35 patients, including 8 deletions and 10 heterozygous, 1 homozygous and 1 compound-heterozygous SNVs. The main clinical characteristics of these patients were being born small for gestational age (90.9%), short stature (88.2%) and microcephaly (74.1%). Feeding difficulties and varying degrees of developmental delay were highly prevalent (54.5%). There were no differences in phenotypes between patients with deletions and SNVs of IGF1R. Functional studies showed that the SNVs tested were associated with decreased AKT phosphorylation. CONCLUSION: We report eight new pathogenic variants of IGF1R and an original case with a homozygous SNV. We found the recently proposed clinical score to be accurate for the diagnosis of IGF1R defects with a sensitivity of 95.2%. We developed an efficient functional test to assess the pathogenicity of SNVs, which is useful, especially for VUS.