Evaluation and management of neonatal onset hyperinsulinemic hypoglycemia: a single neonatal center experience.

OBJECTIVES: To evaluate the clinical characteristics and treatment options of neonates requiring prolonged hospitalization due to persistent hyperinsulinemic hypoglycemia (HH). METHODS: This retrospective cohort study included infants >34 weeks of gestation at birth who were born in our hospital between 2018 and 2021, diagnosed with HH, and required diazoxide within the first 28 days of life. The baseline clinical characteristics, age at the time of diagnosis and treatment options in diazoxide resistance cases were recorded. Genetic mutation analysis, if performed, was also included. RESULTS: A total of 32 infants diagnosed with neonatal HH were followed up. Among the cohort, 25 infants were classified as having transient form of HH and seven infants were classified as having congenital hyperinsulinemic hypoglycemia (CHI). Thirty-one percent of the infants had no risk factors. The median birth weight was significantly higher in the CHI group, whereas no differences were found in other baseline characteristics. Patients diagnosed with CHI required higher glucose infusion rate, higher doses, and longer duration of diazoxide treatment than those in the transient HH group. Eight patients were resistant to diazoxide, and six of them required treatment with octreotide and finally sirolimus. Sirolimus prevented the need of pancreatectomy in five of six patients without causing major side effects. Homozygous mutations in the ABCC8 gene were found in four patients with CHI. CONCLUSIONS: The risk of persistent neonatal hyperinsulinism should be considered in hypoglycemic neonates particularly located in regions with high rates of consanguinity. Our study demonstrated sirolimus as an effective treatment option in avoiding pancreatectomy in severe cases.

Clinical features of generalized lipodystrophy in Turkey: A cohort analysis.

AIM: To describe the Turkish generalized lipodystrophy (GL) cohort with the frequency of each complication and the death rate during the period of the follow-up. METHODS: This study reports on 72 patients with GL (47 families) registered at different centres in Turkey that cover all regions of the country. The mean ± SD follow-up was 86 ± 78 months. RESULTS: The Kaplan-Meier estimate of the median time to diagnosis of diabetes and/or prediabetes was 16 years. Hyperglycaemia was not controlled in 37 of 45 patients (82.2%) with diabetes. Hypertriglyceridaemia developed in 65 patients (90.3%). The Kaplan-Meier estimate of the median time to diagnosis of hypertriglyceridaemia was 14 years. Hypertriglyceridaemia was severe (≥ 500 mg/dl) in 38 patients (52.8%). Seven (9.7%) patients suffered from pancreatitis. The Kaplan-Meier estimate of the median time to diagnosis of hepatic steatosis was 15 years. Liver disease progressed to cirrhosis in nine patients (12.5%). Liver disease was more severe in congenital lipodystrophy type 2 (CGL2). Proteinuric chronic kidney disease (CKD) developed in 32 patients (44.4%) and cardiac disease in 23 patients (31.9%). Kaplan-Meier estimates of the median time to diagnosis of CKD and cardiac disease were 25 and 45 years, respectively. Females appeared to have a more severe metabolic disease, with an earlier onset of metabolic abnormalities. Ten patients died during the follow-up period. Causes of death were end-stage renal disease, sepsis (because of recurrent intestinal perforations, coronavirus disease, diabetic foot infection and following coronary artery bypass graft surgery), myocardial infarction, heart failure because of dilated cardiomyopathy, stroke, liver complications and angiosarcoma. CONCLUSIONS: Standard treatment approaches have only a limited impact and do not prevent the development of severe metabolic abnormalities and early onset of organ complications in GL.

Metreleptin Treatment in a Boy with Congenital Generalized Lipodystrophy due to Homozygous c.465_468delGACT (p.T156Rfs*8) Mutation in the BSCL2 Gene: Results From the First-year

Congenital generalized lipodystrophy (CGL) is a rare, autosomal recessive disorder characterized by an almost complete absence of body fat. In CGL, patients may have hyperphagia due to leptin deficiency. Recombinant human leptin (metreleptin) has been suggested as an effective treatment option. We present successful treatment with metreleptin in a boy with CGL and results from the first year of follow-up. An eight-month-old boy presented with excessive hair growth and a muscular appearance. On examination he had hypertrichosis, decreased subcutaneous adipose tissue over the whole body and hepatomegaly. Laboratory investigations revealed hypertriglyceridemia, hyperinsulinemia, elevated liver transaminases and low leptin levels. Molecular genetic analysis detected a homozygous, c.465_468delGACT (p.T156Rfs*8) mutation in the BSCL2 gene. A diagnosis of CGL type 2 was considered. Despite dietary intervention, exercise, and treatment with additional omega-3 and metformin, the hypertriglyceridemia, hyperinsulinemia, and elevated liver transaminase levels worsened. Metreleptin treatment was started and after one year hyperphagia had disappeared, and there was dramatic improvement in levels of insulin, hemoglobin A1c, triglycerides and liver transaminases. Hepatosteatosis was lessened and hepatosplenomegaly was much improved. Metreleptin appears to be an effective treatment option in children with CGL that remarkably improved metabolic complications in the presented case. Initiation of metreleptin treatment in the early period may decrease mortality and morbidity, and increase the quality of life in children with CGL.

Recommendations for Clinical Decision-making in Children with Type 1 Diabetes and Celiac Disease: Type 1 Diabetes and Celiac Disease Joint Working Group Report

It is well-known that in children with type 1 diabetes (T1D), the frequency of Celiac disease (CD) is increased due to mechanisms which are not fully elucidated but include autoimmune injury as well as shared genetic predisposition. Although histopathologic examination is the gold standard for diagnosis, avoiding unnecessary endoscopy is crucial. Therefore, for both clinicians and patients' families, the diagnosis of CD remains challenging. In light of this, a joint working group, the Type 1 Diabetes and Celiac Disease Joint Working Group, was convened, with the aim of reporting institutional data and reviewing current international guidelines, in order to provide a framework for clinicians. Several controversial issues were discussed: For CD screening in children with T1D, regardless of age, it is recommended to measure tissue transglutaminase-immunoglobulin A (tTG-IgA) and/or endomysial-IgA antibody due to their high sensitivity and specificity. However, the decision-making process based on tTG-IgA titer in children with T1D is still debated, since tTG-IgA titers may fluctuate in children with T1D. Moreover, seronegativity may occur spontaneously. The authors' own data showed that most of the cases who have biopsy-proven CD had tTG-IgA levels 7-10 times above the upper limit. The decision for endoscopy based solely on tTG-IgA levels should be avoided, except in cases where tTG-IgA levels are seven times and above the upper limit. A closer collaboration should be built between divisions of pediatric endocrinology and gastroenterology in terms of screening, diagnosis and follow-up of children with T1D and suspicious CD.

Frequency of Celiac Disease and Spontaneous Normalization Rate of Celiac Serology in Children and Adolescent Patients with Type 1 Diabetes

Objective: The prevalence of celiac disease (CD) varies between 1% and 10% in patients with type 1 diabetes mellitus (T1DM). This study aimed to determine the frequency of spontaneous recovery of celiac serology and the biopsy-proven CD (BPCD) frequency in patients with T1DM. Methods: The data of 668 patients with available celiac serology tests from a total of 779 patients who were followed for the last 10 years with the diagnosis of T1DM were retrospectively evaluated. Results: Positive serology was detected in 103 out of 668 (15.4%) patients. There was spontaneous normalization in 24 (23.3%), fluctuation in 11 (10.7%) and permanently positive serology in 68 (66%). In 46 out of 53 (86.8%) patients with positive serology and biopsy, CD diagnosis was confirmed by biopsy (BPCD). The frequency of BPCD was 6.9%, and the serology in 76.1% was positive at the time of diagnosis of T1DM. The weight, height and body mass index-standard deviation score at diagnosis were lower in patients with BPCD compared to the group without CD. An anti-tissue transglutaminase-IgA (anti-TTG-IgA) level of 11.8 times the upper limit of normal was the most sensitive (93%) and specific (90%) cut-off for BPCD (area under the curve: 0.95; 95% confidence interval: 0.912-1; p<0.001). Conclusion: In our cohort, the frequency of positive serology for CD was 15.4%, while the rate of BPCD was 6.9%. The majority (97.8%) of cases were diagnosed within the first five years of T1DM. In 23.3% of cases, positive anti-TTG-IgA spontaneously resolved without a gluten-free diet (GFD). Therefore, serological follow-up instead of immediate duodenal biopsy or GFD therapy, particularly for patients with asymptomatic and mild anti-TTG IgA level, is warranted.

Clinical Characteristics of 46,XX Males with Congenital Adrenal Hyperplasia

Objective: To retrospectively evaluate the follow-up data in patients with 46,XX congenital adrenal hyperplasia (CAH) who were raised male. Methods: A national database was created. The data of patients were asked to be recorded in the data form. Results: The median (range) age of diagnosis was three (0.1-18.3) years in 44 patients. Twenty nine cases were diagnosed after the age of two years. Most (95.4%) cases were stage 4-5 virilized. Hysterectomy and bilateral salpingoopherectomy, at a median age of 7.25 (2.4-25.3) years, was performed in 35 cases. Testicular prostheses were placed in 11 (25%) cases at a median age of 11.2 (2.8-17) years. The median final height was 149.2 (132.8-172) cms in 38 patients, including simple virilizing (n=18), salt-wasting (n=6), and 11-beta hydroxylase (n=12). Of the 16 patients above the age of eighteen, university education was completed in 25%. Conclusion: It was seen that most (65.9%) of the 46,XX CAH cases raised male were diagnosed after two years of age. In these cases, hysterectomy and bilateral salpingoopherectomy, genital corrective surgeries and testicular prosthesis operations were performed in a very wide age rage.

Evaluation of the Final Adult Height and Its Determinants in Patients with Growth Hormone Deficiency: A Single-centre Experience from the South-Eastern Region of Turkey

Objective: The aim was to determine the final adult height (FAH) achieved by recombinant human growth hormone (rhGH) treatment, the factors affecting FAH and the success of attaining the genetic potential. Methods: Data of 133 patients treated with rhGH therapy were reviewed retrospectively. Patients were grouped according to diagnosis, either isolated GH deficiency (IGHD) or multiple pituitary hormone deficiency (MPHD), and by sex, and pubertal status at the beginning of treatment. Results: The mean age of initiation of treatment was 12.3±2.18 years, and the mean duration of rhGH treatment was 3.65±1.5 years. The mean height standard deviation score (SDS) at diagnosis was -3.11±0.75 SD. All patients received a standardized GH dose of 0.033 mg/kg/day. Mean FAH-SDS was -1.8±0.77 and delta height-SDS (the change in height SDS between the beginning and end of treatment) was 1.28±0.94 SD. FAH-SDS was -1.79±0.86 SD in males; -1.82±0.64 in females (p=0.857); -1.94±0.71 at the beginning of treatment in pubertal patients and -1.68±0.81 in prepubertal patients (p=0.056); -1.84±0.89 in patients with IGHD and -0.47±0.2 in patients with MPHD (p˃0.05). In multiple regression analysis, First year delta height-SDS was the most predictive factor for both FAH-SDS and delta height-SDS. Conclusion: The majority of our patients achieved a final height compatible with their genetic potential as well as population standards when treated with rhGH even having started at a relatively late age. First year delta height-SDS was a predictive factor for FAH.

Ectopic Posterior Pituitary, Polydactyly, Midfacial Hypoplasia and Multiple Pituitary Hormone Deficiency due to a Novel Heterozygous IVS11-2A>C(c.1957-2A>C) Mutation in the GLI2 Gene

A novel heterozygous IVS11-2A>C(c.1957-2A>C) mutation in the GLI2 gene is reported. There was an extremely distinct phenotypical expression in two siblings and their father. The index case was a boy who developed cholestasis and hypoglycaemia in the neonatal period. He had bilateral postaxial polydactyly, mid-facial hypoplasia, high palatal arch, micropenis, and bilateral cryptorchidism. Laboratory examination revealed a diagnosis of multiple pituitary hormone deficiency. There was severe anterior pituitary hypoplasia, absent pituitary stalk and ectopic posterior pituitary on magnetic resonance imaging which suggested pituitary stalk interruption syndrome with no other midline structural abnormality. Molecular genetic analysis revealed a novel heterozygous splicing IVS11-2A>C(c.1957-2A>C) mutation detected in the GLI2 gene. His father and a six-year-old brother with the identical mutation also had unilateral postaxial polydactyly and mid-facial hypoplasia although there was no pituitary hormone deficiency. This novel heterozygous GLI2 mutation detected appears to present with an extremely variable clinical phenotype, even in related individuals with an identical mutation, suggesting incomplete penetrance of this GLI2 mutation.

Response to growth hormone treatment in very young patients with growth hormone deficiencies and mini-puberty.

BACKGROUND: The aim of the study was to assess the response to growth hormone (GH) treatment in very young patients with GH deficiency (GHD) through a national, multi-center study. Possible factors affecting growth response were assessed (especially mini-puberty). METHODS: Medical reports of GHD patients in whom treatment was initiated between 0 and 3 years of age were retrospectively evaluated. RESULTS: The cohort numbered 67. The diagnosis age was 12.4±8.6 months, peak GH stimulation test response (at diagnosis) as 1.0±1.4 ng/mL. The first and second years length gain was 15.0±4.3 and 10.4±3.4 cm. Weight gain had the largest effect on first year growth response; whereas weight gain and GH dose were both important factors affecting second year growth response. In the multiple pituitary hormone deficiency (MPHD) group (n=50), first year GH response was significantly greater than in the isolated GH deficiency (IGHD) group (n=17) (p=0.030). In addition first year growth response of infants starting GH between 0 and 12 months of age (n=24) was significantly greater than those who started treatment between 12 and 36 months of age (n=43) (p<0.001). These differences were not seen in the second year. Δ Length/height standard deviation score (SDS), Δ body weight SDS, length/height SDS, weight SDS in MPHD without hypogonadism for the first year of the GH treatment were found as significantly better than MPHD with hypogonadism. CONCLUSIONS: Early onsets of GH treatment, good weight gain in the first year of the treatment and good weight gain-GH dose in the second year of the treatment are the factors that have the greatest effect on length gain in early onset GHD. The presence of the sex steroid hormones during minipubertal period influence growth pattern positively under GH treatment (closer to the normal percentage according to age and gender).

Sirolimus-Induced Hepatitis in Two Patients with Hyperinsulinemic Hypoglycemia

Sirolimus has been reported to be effective in the treatment of the diffuse form of congenital hyperinsulinism (CHI), unresponsive to diazoxide and octreotide, without causing severe side effects. Two newborns with CHI due to homozygous ABCC8 gene mutations were started on sirolimus aged 21 and 17 days, due to lack of response to medical treatment. A good response to sirolimus was observed. At follow-up after ten and two months of treatment, liver enzymes were found to be increased [serum sirolimus level 1.4 ng/mL (normal range: 5-15), aspartate aminotransferase (AST): 298U/L, alanine aminotransferase (ALT): 302U/L and serum sirolimus level: 9.9 ng/mL, AST: 261U/L, ALT: 275U/L, respectively]. In Case 1, discontinuation of the drug resulted in normalization of liver enzymes within three days. Two days after normalization, sirolimus was restarted at a lower dose, which resulted in a repeated increase in transferases. In Case 2, a reduction of sirolimus dose caused normalization of liver enzymes within ten days. When the dose was increased, enzymes increased within three days. Sirolimus was discontinued in both cases. The rapid normalization of liver enzyme levels after sirolimus withdrawal or dose reduction; elevation of transaminases after restart or dose increase and rapid normalization after sirolimus withdrawal were findings strongly suggestive of sirolimus-induced hepatitis. To the best of our knowledge, this is the first report of sirolimus-induced hepatitis in CHI. Sirolimus is a promising drug for CHI patients who are unresponsive to medical treatment, but physicians should be vigilant for adverse effects on liver function.

Clinical characteristics and molecular genetic analysis of 22 patients with neonatal diabetes from the South-Eastern region of Turkey: predominance of non-KATP channel mutations.

BACKGROUND: Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes and usually presents in the first 6 months of life. We aimed to describe the clinical characteristics and molecular genetics of a large Turkish cohort of NDM patients from a single centre and estimate an annual incidence rate of NDM in South-Eastern Anatolian region of Turkey. DESIGN AND METHODS: NDM patients presenting to Diyarbakir Children State Hospital between 2010 and 2013, and patients under follow-up with presumed type 1 diabetes mellitus, with onset before 6 months of age were recruited. Molecular genetic analysis was performed. RESULTS: Twenty-two patients (59% males) were diagnosed with NDM (TNDM-5; PNDM-17). Molecular genetic analysis identified a mutation in 20 (95%) patients who had undergone a mutation analysis. In transient neonatal diabetes (TNDM) patients, the genetic cause included chromosome 6q24 abnormalities (n=3), ABCC8 (n=1) and homozygous INS (n=1). In permanent neonatal diabetes (PNDM) patients, homozygous GCK (n=6), EIF2AK3 (n=3), PTF1A (n=3), and INS (n=1) and heterozygous KCNJ11 (n=2) mutations were identified. Pancreatic exocrine dysfunction was observed in patients with mutations in the distal PTF1A enhancer. Both patients with a KCNJ11 mutation responded to oral sulphonylurea. A variable phenotype was associated with the homozygous c.-331C>A INS mutation, which was identified in both a PNDM and TNDM patient. The annual incidence of PNDM in South-East Anatolian region of Turkey was one in 48 000 live births. CONCLUSIONS: Homozygous mutations in GCK, EIF2AK3 and the distal enhancer region of PTF1A were the commonest causes of NDM in our cohort. The high rate of detection of a mutation likely reflects the contribution of new genetic techniques (targeted next-generation sequencing) and increased consanguinity within our cohort.

Molecular analysis of PROP1, POU1F1, LHX3, and HESX1 in Turkish patients with combined pituitary hormone deficiency: a multicenter study.

To investigate the specific mutations in PROP1, POU1F1, LHX3, and HESX1 genes in patients with combined pituitary hormone deficiency (CPHD) in Turkey. Seventy-six patients with CPHD were included in this study. Based on clinical, hormonal, and neuro-radiological data, relevant transcription factor genes were evaluated by Sanger sequencing and multiplex ligation-dependent probe amplification. Total frequency of mutations was 30.9 % in patients with CPHD. Frequency was significantly higher in familial patients (p = 0.001). Three different types of mutations in PROP1 gene (complete gene deletion, c.301-302delAG, a novel mutation; IVS1+2T>G) were found in 12 unrelated patients (21.8 %). Mutations in PROP1 gene were markedly higher in familial than in sporadic cases (58.8 vs. 5.3 %, p < 0.001). Homozygous complete gene deletion was the most common mutation in PROP1 gene (8/12) and was identified in six familial patients. Four different homozygous mutations [p.Q4X, novel mutations; exons 1-2 deletion, p.V153F, p.I244S] were detected in POU1F1 gene. Central precocious puberty was firstly observed in a sporadic-male patient with homozygous POU1F1 (p.I244S) mutation. A homozygous mutation in HESX1 gene (p.R160H) was detected in one patient. This study is the first to investigate specific mutations in CPHD patients in Turkey. Complete deletion in PROP1 gene was the most common mutation encountered in patients with CPHD. We believe that the results of this study will contribute to the establishment of genetic screening strategies in Turkey, as well as to the studies on phenotype-genotype correlations and early diagnosis of CPHD patients.

Prepubertal unilateral gynecomastia: report of 2 cases.

Prepubertal unilateral gynecomastia is an extremely rare condition. At present, its etiology and management strategy are not well known. Two unrelated prepubertal boys of ages 8 and 9 who presented with complaints of unilateral enlargement of breast tissue are reported. Physical examination, biochemical, hormonal and oncologic work-up findings were normal. Both patients were treated with peripheral liposuction successfully. Histopathological and immunohistochemical examinations showed benign fibroglandular gynecomastia and intensive (3+) estrogen receptor expression in 100% of periductal epithelial cells. Although an extremely rare and generally benign condition, patients with prepubertal unilateral gynecomastia should have a full endocrine and oncologic work-up.

Familial isolated growth hormone deficiency due to a novel homozygous missense mutation in the growth hormone releasing hormone receptor gene: clinical presentation with hypoglycemia.

CONTEXT: Mutations in the growth hormone releasing hormone receptor (GHRHR) gene are a relatively rare cause of isolated growth hormone deficiency (IGHD). OBJECTIVE: This study aimed to understand the biochemical basis of hypoglycemia in the index case and the molecular basis of severe short stature in a large consanguineous family with IGHD. PATIENTS AND METHODS: The index case presented with a hypoglycemic convulsion, following which eight members in two related consanguineous Turkish families were identified with IGHD. Homozygosity mapping identified the homozygous regions shared only among the affected individuals. Sanger sequencing of GHRHR, which resided in the shared homozygous region, was performed. In silico analysis of the pathogenic GHRHR variant was performed. RESULTS: The clinical presentation and hormonal analysis confirmed GH deficiency in all affected individuals. Magnetic resonance imaging scan of the pituitary gland showed anterior pituitary hypoplasia in five affected individuals in which the youngest was only 0.4 years old, but with normal pituitary size in three affected individuals. Homozygosity mapping showed two large homozygous regions on chromosome 7 shared only among affected individuals. Sanger sequencing of GHRHR gene present in one of these shared regions identified a novel homozygous missense mutation (p.C64G) segregating with the disease phenotype. In silico analysis predicted the mutation to be deleterious and disease causing. CONCLUSIONS: We describe a large consanguineous Turkish kindred with IGHD due to a novel homozygous missense GHRHR mutation. This is the first description of presentation with hypoglycemia and the earliest reported occurrence of anterior pituitary hypoplasia in patients with GHRHR mutation.

Clinical characteristics and phenotype-genotype analysis in Turkish patients with congenital hyperinsulinism; predominance of recessive KATP channel mutations.

OBJECTIVE: Congenital hyperinsulinism (CHI) is the commonest cause of hyperinsulinaemic hypoglycaemia in the neonatal, infancy and childhood periods. Its clinical presentation, histology and underlying molecular biology are extremely heterogeneous. The aim of this study was to describe the clinical characteristics, analyse the genotype-phenotype correlations and describe the treatment outcome of Turkish CHI patients. DESIGN AND METHODS: A total of 35 patients with CHI were retrospectively recruited from four large paediatric endocrine centres in Turkey. Detailed clinical, biochemical and genotype information was collected. RESULTS: Diazoxide unresponsiveness was observed in nearly half of the patients (n=17; 48.5%). Among diazoxide-unresponsive patients, mutations in ABCC8/KCNJ11 were identified in 16 (94%) patients. Among diazoxide-responsive patients (n=18), mutations were identified in two patients (11%). Genotype-phenotype correlation revealed that mutations in ABCC8/KCNJ11 were associated with an increased birth weight and early age of presentation. Five patients had p.L1171fs (c.3512del) ABCC8 mutations, suggestive of a founder effect. The rate of detection of a pathogenic mutation was higher in consanguineous families compared with non-consanguineous families (87.5 vs 21%; P<0.0001).Among the diazoxide-unresponsive group, ten patients were medically managed with octreotide therapy and carbohydrate-rich feeds and six patients underwent subtotal pancreatectomy. There was a high incidence of developmental delay and cerebral palsy among diazoxide-unresponsive patients. CONCLUSIONS: This is the largest study to report genotype-phenotype correlations among Turkish patients with CHI. Mutations in ABCC8 and KCNJ11 are the commonest causes of CHI in Turkish patients (48.6%). There is a higher likelihood of genetic diagnosis in patients with early age of presentation, higher birth weight and from consanguineous pedigrees.

Multiple pituitary hormone deficiency due to gunshot injury in a 6-year-old girl.

Gunshot injuries (GSI) of the cranial area have an extremely high mortality rate. Herein, we present a girl who has been living with a bullet in the posterior sellar region. A 6-year-old girl was admitted with complaints of headache, polyuria and polydypsia, which started after a GSI. At the time of admission the patient's anthropometric, physical and neurological examinations were normal. Urine output was 5.5 L/m2/24h. A water deprivation test suggested central diabetes insipidus, which responded to treatment. Evaluation of other pituitary hormones revealed central hypothyroidism and growth hormone deficiency. Pituitary hormone deficiency must be kept in mind in patients injured by a gunshot to the sellar/parasellar region.

Distribution of gene mutations associated with familial normosmic idiopathic hypogonadotropic hypogonadism.

OBJECTIVE: Normosmic idiopathic hypogonadotropic hypogonadism (nIHH) is characterized by failure of initiation or maintenance of puberty due to insufficient gonadotropin release, which is not associated with anosmia/hyposmia. The objective of this study was to determine the distribution of causative mutations in a hereditary form of nIHH. METHODS: In this prospective collaborative study, 22 families with more than one affected individual (i.e. multiplex families) with nIHH were recruited and screened for genes known or suspected to be strong candidates for nIHH. RESULTS: Mutations were identified in five genes (GNRHR, TACR3, TAC3, KISS1R, and KISS1) in 77% of families with autosomal recessively inherited nIHH. GNRHR and TACR3 mutations were the most common two causative mutations occurring with about equal frequency. CONCLUSIONS: Mutations in these five genes account for about three quarters of the causative mutations in nIHH families with more than one affected individual. This frequency is significantly greater than the previously reported rates in all inclusive (familial plus sporadic) cohorts. GNRHR and TACR3 should be the first two genes to be screened for diagnostic purposes. Identification of causative mutations in the remaining families will shed light on the regulation of puberty.

A homozygous recurring mutation in WISP3 causing progressive pseudorheumatoid arthropathy.

WISP3 is a member of the CCN (for CTGF, CYR61, and NOV) gene family, which encodes cysteine-rich secreted proteins with roles in cell growth and differentiation. Mutations in the WISP3 gene are associated with the autosomal recessive skeletal disorder, also known as progressive pseudorheumatoid arthropathy of childhood (PPAC). We diagnosed three siblings from a non-consanguineous family with PPAC. The patients were asymptomatic in early childhood. Signs and symptoms of disease that include progressive joint stiffness, swelling of the finger joints, and osteopenia, and slow linear growth developed between 2 and 8 years of age. PCR amplification and direct sequencing of the WISP3 gene revealed a homozygous mutation at nucleotide 156 of the WISP3 gene, resulting in a Cys52-to-ter substitution. This mutation has previously been reported in French, Italian, and Arab families. Interestingly, the C52X mutation was found to be associated with a c.248G-->A (G83E) variation, suggesting the existence of a founder effect. By contrast, the presence of the same aberration in three different ethnic groups could imply that this particular site is prone to mutation. Basal fasting concentrations of growth hormone, insulin-like growth factor-1, and insulin-like growth factor binding protein-3, as well as glucose and insulin levels revealed no aberrations. In conclusion, consideration of this rare disease that causes significant morbidity with short stature, osteopenia and arthritic complaints would prevent unnecessary examinations and treatment attempts. Testing for this specific mutation in suspected cases could provide a rapid and definitive diagnosis.