Resolved Severe Primary Hypothyroidism in Sensenbrenner Syndrome Post Hepatorenal Transplantation: A Case Report.

INTRODUCTION: Sensenbrenner syndrome, or cranioectodermal dysplasia (OMIM #218330), is a rare genetic condition inherited as an autosomal recessive with less than 70 reported cases worldwide. It results in multiorgan abnormalities along with ectodermal structural defects. No previous reported cases demonstrated primary hypothyroidism in a matter of Sensenbrenner syndrome. CASE PRESENTATION: Herein, we report a 6-year-old girl who suffered from progressive liver failure and end-stage renal disease secondary to Sensenbrenner syndrome, which was associated with severe primary hypothyroidism that completely recovered after a combined renal and liver transplant. CONCLUSION: For the first time in the literature, we report an association of Sensenbrenner syndrome with hypothyroidism that resolved after a combined renal and liver transplant. Such findings expand the clinical spectrum of this syndrome. However, a larger cohort is needed to confirm or exclude such an association. Our case highlights the importance of thyroid function monitoring in any patient with renal and liver failure prior to and after a hepatorenal transplant.

Frequency and Risk Factors of Diabetic Ketoacidosis in a Specialized Children's Hospital, Riyadh: A Cross-sectional Study.

Objectives: Diabetic ketoacidosis (DKA) is a life-threatening complication and a leading cause of hospitalization in patients with type 1 diabetes mellitus (T1DM). We aimed to assess the risk factors of admissions of children with DKA in a specialized children's hospital to reduce morbidity and inform appropriate prevention and intervention strategies. Methods: We conducted a retrospective review of all DKA admissions at King Abdullah Specialized Children's Hospital, Riyadh (March 2015-December 2017). Data were gathered from newly diagnosed patients with T1DM and known patients ≤ 14 years old with DKA criteria. The main variables were frequency, precipitating factors, and other characteristics of DKA admissions in both groups. Results: A total of 116/562 patients with T1DM (mean age 8.9±3.0 years) had 146 DKA episodes, of which 42/116 (36.2%) were newly diagnosed. The frequency of DKA admissions were 146/562 (26.0%), of which 42/141 (29.8%) were newly diagnosed versus 104/421 (24.7%) known T1DM patients. The majority were 10-14 years old (p ≤ 0.001), and 77.8% were females. Missing insulin was the main cause of DKA (p = 0.001) among known patients with T1DM. Recurrent episodes (n = 30/146, 20.5%) occurred in 15/116 patients and were more common in children ≥ 10 years of age (p = 0.024). The mean length of stay was 2.6±2.0 days and increased with DKA severity (p = 0.008). Conclusions: Most DKA episodes were in patients with known T1DM and missing insulin was the leading cause of DKA. In addition to awareness campaigns to prevent DKA as an initial presentation, intervention strategies should also target high-risk groups of known patients of T1DM such as adolescents and patients with recurrent episodes.

Patients' Perception of the Use of the EasyPod™ Growth Hormone Injector Device and Impact on Injection Adherence: A Multi-Center Regional Study.

Objective: This study aimed to assess patient perceptions of the use of the EasyPod™ growth hormone delivery device and its association with compliance. Methods: This cross-sectional, multicenter study was conducted in six centers from three countries (United Arab Emirates, Oman, and Saudi Arabia,) between March 2020 and June 2020. Children and adolescents aged 3-18 years, diagnosed with growth disorders and receiving rhGH through the EasyPod™ device were enrolled. Patients and caregivers were given a pre-set questionnaire that evaluated patient satisfaction, preference for technical and personalized features, and device drawbacks. The results were analyzed using independent measures of analysis of variance to evaluate the association of higher satisfaction with device features and better compliance. Results: A total of 186 patients were enrolled in the study. Of these, 45.7% had GH deficiency. The mean age (±SD) of patients was 11.8 (±2.76) years; 117 (62.90%) were males. Average compliance was 87%. One hundred patients (53.76%) had injection compliance of ≥90%. Amongst these patients, 74%, 68%, and 77% top-scored (5/5) the technical features of hidden needle, skin sensor, and pre-set dosing, respectively, compared to top scores by 39%, 34%, and 51% patients in the <90% compliance group (p-value <0.05). Similarly, a statistically significant difference was observed between the groups (p-value <0.05) in the perception of the usefulness of the tracking features such as display of history of injected doses (78% vs. 47.7%), a reminder for medicine remaining (46% vs. 23.3%) and battery power indicator (48% vs. 20.9%). Personal screen messages were associated with higher compliance while the requirement to keep the device in the fridge was reported as the most inconvenient feature by 56% of patients in the higher compliance group as against 39.5% in the lower compliance group (p-value <0.05). There was no statistically significant difference in the intensity of pain reported in the two compliance groups. Conclusion: Our study showed that there is a statistically significant association between better perception of device features and higher compliance.

Achieving Optimal Short- and Long-term Responses to Paediatric Growth Hormone Therapy

It is over sixty years since the first administration of human growth hormone (GH) to children with GH deficiency, and over thirty years since recombinant human GH has been available for treatment of GH deficiency and a wider range of non-GH deficiency disorders. From a diagnostic perspective, genetic analysis, using single gene or Sanger sequencing and more recently next generation or whole exome sequencing, has brought advances in the diagnosis of specific causes of short stature, which has enabled therapy to be targeted more accurately. Genetic discoveries have ranged from defects of pituitary development and GH action to abnormalities in intracellular mechanisms, paracrine regulation and cartilage matrix formation. The strategy of GH therapy using standard doses has evolved to individualised GH dosing, depending on diagnosis and predictors of growth response. Evidence of efficacy of GH in GH deficiency, Turner syndrome and short children born small for gestational age is reviewed. The importance of critical assessment of growth response is discussed, together with the recognition and management of a poor or unsatisfactory growth response and the organisational issues related to prevention, detection and intervention regarding suboptimal adherence to GH therapy.

Sirolimus in the treatment of three infants with diffuse congenital hyperinsulinism.

BACKGROUND: Congenital hyperinsulinism (CHI) is a major cause of persistent hypoglycemia and brain damage. Therapeutic strategies to avoid near total pancreatectomy in patients who are unresponsive to maximum doses of diazoxide and octreotide remain to be identified, although sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been used successfully to treat diffuse type CHI. CASE PRESENTATION: We used sirolimus to treat three infants with diffuse CHI. Diagnosis was confirmed clinically, biochemically and by genetic testing. Homozygous mutations in KCNJ11, ABCC8 and KCNJ11 were identified in infants 1, 2 and 3, respectively. Each infant had received the therapy for at least 2 months with close monitoring of glycemic response, serum insulin and C-peptide. None of the infants responded to the therapy. CONCLUSIONS: We conclude that sirolimus is less effective in the treatment of diffuse CHI in patients with severe mutations in the homozygous state compared with those with the mutations in the heterozygous.

Growth hormone therapy and treatment outcomes: current clinical practice of the Gulf Cooperation Council.

Over the last 20 years, recombinant human growth hormone (somatropin) has been the cornerstone of managing children with growth hormone deficiency (GHD). Although both international and national guidelines for growth hormone (GH) therapy exist, there is currently no consensus on the optimal use of GH therapy in Gulf Cooperation Council (GCC) countries. The goals of GH therapy are to normalize height during childhood, attain normal adult height and correct metabolic abnormalities related to GHD. However, extended use of GH >50 µg/kg/day may increase frequency of adverse events. Here, we report the proceedings from a meeting of nine GCC pediatric endocrinology experts, which took place in Beirut in November 2011. The meeting was also attended by three European counterparts and aimed to provide consensus on best practice in the management of children with GHD in the GCC based on current local medical and regulatory environments.

Pubertal characteristics among schoolgirls in Riyadh, Saudi Arabia.

Puberty is the gradual transition period between childhood and adulthood. Many factors may contribute to the onset of puberty. The objective of the study was to determine the age of onset of secondary pubertal characteristics among Saudi Arabian girls. A cross-sectional study was conducted using a cluster sample design. Seven hundred and twenty-five schoolgirls between the ages of 6 and 16 years from diverse socioeconomic levels were included. During physical examinations, the height and weight of the girls were recorded, and the stages of breast and pubic hair development were determined according to Tanner stages; axillary hair development was determined according to modified stages. The median age at Tanner stage 2 for breast and pubic hair development was 10 years. The median age at stage 2 in modified scales for axillary hair development was 12 years. In conclusion, the median age of the onset of breast development at Tanner stage 2 for Saudi girls in Riyadh is lower than what has been reported in some countries in Europe, South Africa, Turkey and India but similar to girls in Hong Kong, China and white girls in the USA, which may support secular trends of an earlier onset of puberty.

Variable phenotype in five patients with Wolcott-Rallison syndrome due to the same EIF2AK3 (c.1259delA) mutation.

Wolcott-Rallison syndrome (WRS) is a rare condition characterized by permanent neonatal diabetes (PND), skeletal dysplasia, and recurrent hepatitis. Other features, including central hypothyroidism, have been reported. We compared the phenotype of five patients from two families with WRS caused by the same EIF2AK3 mutation who have been followed up since diagnosis. Direct sequencing of the EIF2AK3 gene identified a homozygous frameshift mutation (c.1259delA) in all patients that has been reported only in these families. All patients presented with PND and four experienced recurrent hepatitis. A 3.5-year-old girl has isolated PND, whereas her younger sister has typical WRS features. Two children developed skeletal abnormalities and two had transient central hypothyroidism. Other reported features of WRS were not detected. The EIF2AK3 c.1259delA mutation results in a variable phenotype, ranging from isolated PND to typical WRS. Thyroid dysfunction in WRS is a transient phenomenon reflecting euthyroid sickness.

Heterogeneity in phenotype of usher-congenital hyperinsulinism syndrome: hearing loss, retinitis pigmentosa, and hyperinsulinemic hypoglycemia ranging from severe to mild with conversion to diabetes.

OBJECTIVE: To evaluate the phenotype of 15 children with congenital hyperinsulinism (CHI) and profound hearing loss, known as Homozygous 11p15-p14 Deletion syndrome (MIM #606528). RESEARCH DESIGN AND METHODS: Prospective clinical follow-up and genetic analysis by direct sequencing, multiplex ligation-dependent probe amplification, and microsatellite markers. RESULTS: Genetic testing identified the previous described homozygous deletion in 11p15, USH1C:c.(90+592)_ABCC8:c.(2694-528)del. Fourteen patients had severe CHI demanding near-total pancreatectomy. In one patient with mild, transient neonatal hypoglycemia and nonautoimmune diabetes at age 11 years, no additional mutations were found in HNF1A, HNF4A, GCK, INS, and INSR. Retinitis pigmentosa was found in two patients aged 9 and 13 years. No patients had enteropathy or renal tubular defects. Neuromotor development ranged from normal to severe delay with epilepsy. CONCLUSIONS: The phenotype of Homozygous 11p15-p14 Deletion syndrome, or Usher-CHI syndrome, includes any severity of neonatal-onset CHI and severe, sensorineural hearing loss. Retinitis pigmentosa and nonautoimmune diabetes may occur in adolescence.

Newborn with dilated cardiomyopathy secondary to vitamin d deficiency.

Hypocalcemia is a rare but reversible cause of dilated cardiomyopathy with limited cases being reported in the literature. Vitamin D deficiency is the main cause of hypocalcemia in almost all reported cases. We report a newborn presented with hypocalcemia-induced dilated cardiomyopathy secondary to vitamin D deficiency. After calcium and vitamin D therapy, the baby showed a rapid recovery of the cardiac function.

Mutation of the CYP2R1 vitamin D 25-hydroxylase in a Saudi Arabian family with severe vitamin D deficiency.

CONTEXT: Inherited forms of vitamin D deficiency are rare causes of rickets and to date have been traced to mutations in three genes, VDR, encoding the 1α,25-dihydroxyvitamin D receptor, CYP27B1, encoding the vitamin D 1α-hydroxylase, and CYP2R1, encoding a microsomal vitamin D 25-hydroxylase. RESULTS: Multiple mutations have been identified in VDR and CYP27B1 in patients with rickets, and thus, the roles of these two genes in vitamin D metabolism are unassailable. The case is less clear for CYP2R1, in which only a single mutation, L99P in exon 2 of the gene, has been identified in Nigerian families, and because multiple enzymes with vitamin D 25-hydroxylase activity have been identified. Here we report molecular genetic studies on two siblings from a Saudi family who presented with classic symptoms of vitamin D deficiency. The affected offspring inherited two different CYP2R1 mutations (367+1, G→A; 768, iT), which are predicted to specify null alleles. CONCLUSION: We conclude that CYP2R1 is a major vitamin D 25-hydroxylase that plays a fundamental role in activation of this essential vitamin.

Puberty development among children and adolescents with chronic disease in Saudi Arabia.

BACKGROUND AND OBJECTIVES: Increasing numbers of children with chronic health conditions are now surviving into adolescence and adulthood because of advancing health care. These chronic health conditions are generally known to impact a child's growth and development, including pubertal development. In Saudi Arabia, chronic diseases are prevalent, yet no reports of pubertal onset and its relation to chronic illness are available. The aim of this study was to explore pubertal development among Saudi children and adolescents with a chronic illness. DESIGN AND SETTING: Cross-sectional study conducted at schools in Riyadh, Saudi Arabia in 2006. SUBJECTS AND METHODS: Those students whose parents reported that their son/daughter had a chronic illness and/or was taking a long-term medication underwent a physical examination to determine sexual maturity rating and growth parameters. RESULTS: Of 1371 students who participated in the study, 155 (11.3%) had a chronic illness. Of those, 79 (51%) were male, and the mean SD age of all the students was 11.4 (2.4) years. Ninety (58%) students were taking medication for their health condition. Bronchial asthma was reported to be the most common chronic condition (n=66; 42.6%), followed by blood disorders (n=41; 26.5%). Fifty-three (34%) students were overweight or obese. For male gonadal (G) development, the mean age of boys with G stage 2 was 11.7 years; stage 3: 13.5 years; stage 4: 14.1 years; and stage 5: 14.6 years. For female breast (B) development, the mean age of girls with B stage 2 was 10.7 years; stage 3: 11.3 years; stage 4: 12.4 years; and stage 5: 14.1 years. The pubic hair development for both boys and girls was similar to the corresponding gonadal or breast development, respectively. CONCLUSIONS: The age of onset of pubertal development for both boys and girls with a chronic illness are within normal limits. The high prevalence of overweight and obesity may contribute to this phenomenon, yet further studies should consider the effects of disease severity and chronicity and medication use as possible confounders.

Four novel cases of permanent neonatal diabetes mellitus caused by homozygous mutations in the glucokinase gene.

Permanent neonatal diabetes mellitus (PNDM) caused by homozygous mutations in the glucokinase gene (GCK) is rare and only eight homozygous GCK mutations have been reported so far. Heterozygous GCK mutations cause maturity-onset diabetes of the young (MODY). We report four patients with growth retardation from two separate families (with three siblings in one family and one patient in another family) presenting with persistent hyperglycaemia within the first two days of life. We found one homozygous non-sense mutation (Q98X) in GCK in three siblings from one family and a homozygous missense GCK mutation (G261R) in one patient from another family. Both mutations have been identified previously in GCK-MODY in the heterozygous state. However, this is the first study to report the homozygous forms of these mutations in PNDM. We report four novel cases of PNDM caused by homozygous GCK mutations, including a non-sense mutation in exon 3 (Q98X) and a missense mutation in exon 7 (G261R).

Successful transfer from insulin to oral sulfonylurea in a 3-year-old girl with a mutation in the KCNJ11 gene.

Neonatal diabetes mellitus is considered a rare disease that is diagnosed in the first six months of life, and can be either transient or permanent. Recent advances in molecular genetics have shown that activating mutations in KCNJ11 (the gene that encodes for the Kir6.2 subunit of the K ATP potassium channel of the pancreatic beta-cell) is a common cause of permanent neonatal diabetes mellitus. Patients with mutations in this gene may respond to oral sulfonylureas. We describe a 3-year-old girl with permanent neonatal diabetes mellitus with a mutation in the KCNJ11 gene (R201H), who was successfully transferred from subcutaneous insulin to oral glibenclamide, with a marked improvement in glycemic control. This is the first successful switch from insulin to oral sulfonylurea in a patient with R201H mutation, in the Arabian Gulf.

Puberty onset among boys in riyadh, saudi arabia.

BACKGROUND: The ages of onset of pubertal characteristics are influenced by genetic, geographic, dietary and socioeconomic factors; however, due to lack of country-specific norms, clinicians in Saudi Arabia use Western estimates as standards of reference for local children. AIMS: The aim of the Riyadh Puberty Study was to provide data on pubertal development to determine the average age of onset of pubertal characteristics among Saudi boys. METHODS: Cross-sectional study among male school children in Riyadh, Saudi Arabia, in 2006, 542 schoolboys, aged 6 to 16 years old, from diverse socioeconomic levels were selected into the sample using a cluster sample design. Tanner stages were ascertained during physical examination by pediatric endocrine consultants, and also trained pediatric residents and fellows. RESULTS: The mean age (standard deviation) at Tanner Stages 2, 3, 4, and 5 for pubic hair development of Saudi boys was 11.4 (1.6), 13.3 (1.3), 14.4 (1.0) and 15.1 (0.8) years old, respectively. For gonadal development, the mean age (standard deviation) at stages 2, 3, 4, and 5 were 11.4 (1.5), 13.3 (1.2), 14.3 (1.1) and 15.0 (0.9) years old, respectively. CONCLUSION: The ages of onset of pubertal characteristics, based on gonadal development, among Saudi boys are comparable to those reported in Western populations.

Wolcott-Rallison syndrome is the most common genetic cause of permanent neonatal diabetes in consanguineous families.

CONTEXT AND OBJECTIVE: Mutations in EIF2AK3 cause Wolcott-Rallison syndrome (WRS), a rare recessive disorder characterized by early-onset diabetes, skeletal abnormalities, and liver dysfunction. Although early diagnosis is important for clinical management, genetic testing is generally performed after the full clinical picture develops. We aimed to identify patients with WRS before any other abnormalities apart from diabetes are present and study the overall frequency of WRS among patients with permanent neonatal diabetes. RESEARCH DESIGN AND METHODS: The coding regions of EIF2AK3 were sequenced in 34 probands with infancy-onset diabetes with a clinical phenotype suggestive of WRS (n = 28) or homozygosity at the WRS locus (n = 6). RESULTS: Twenty-five probands (73.5%) were homozygous or compound heterozygous for mutations in EIF2AK3. Twenty of the 26 mutations identified were novel. Whereas a diagnosis of WRS was suspected before genetic testing in 22 probands, three patients with apparently isolated diabetes were diagnosed after identifying a large homozygous region encompassing EIF2AK3. In contrast to nonconsanguineous pedigrees, mutations in EIF2AK3 are the most common known genetic cause of diabetes among patients born to consanguineous parents (24 vs. < 2%). Age at diabetes onset and birth weight might be used to prioritize genetic testing in the latter group. CONCLUSIONS: WRS is the most common cause of permanent neonatal diabetes mellitus in consanguineous pedigrees. In addition to testing patients with a definite clinical diagnosis, EIF2AK3 should be tested in patients with isolated neonatal diabetes diagnosed after 3 wk of age from known consanguineous families, isolated populations, or countries in which inbreeding is frequent.

Hypoparathyroidism-retardation-dysmorphism (HRD) syndrome in triplets.

We report female triplets with the clinical and biochemical manifestations of hypoparatyroidism-retardation-dysmorphism (HRD) syndrome also known as Sanjad-Sakati syndrome. They were born at 35 weeks gestation after assisted pregnancy (in vitro fertilization). The parents are first degree cousins from Saudi Arabia.

The syndrome of septo-optic dysplasia in Saudi children.

OBJECTIVE: To describe the clinical, ophthalmological, endocrinological and radiological features of 10 Saudi children with the syndrome of septo-optic dysplasia and hypothalamic hypopituitarism. METHODS: All patients underwent complete ophthalmological and endocrinological evaluation at the Pediatric Endocrine Clinics, King Faisal Specialist Hospital and Research Center and King Fahad National Guard Hospital, Riyadh, Kingdom of Saudi Arabia, from October 1999 through to May 2004. The hormonal evaluation included growth hormone, adrenocorticotrophic hormone, thyroid stimulating hormone, gonadotropin and anti diuretic hormone testing, and the neuroradiological assessment included brain magnetic resonance imaging or computed tomogram scanning, or both. RESULTS: The current age of patients ranged from 18- months to 5-years. The mean age of initial presentation for endocrine evaluation was 14-months. Hormonal studies indicated that all children had multiple pituitary hormone deficiencies (2 or more of the pituitary hormones were deficient). Ten children had growth hormone deficiency, 8 had thyroid stimulating hormone deficiency, 8 had adrenocorticotrophic hormone deficiency, 2 children were suspected to have gonadotropin deficiency and central diabetes insipidus was present in one patient. Pendular nystagmus and impaired vision were common initial signs. All children had bilateral optic nerve hypoplasia. Neuroradiologic findings were variable. Eight children had absent septum pellucidum, 3 had pituitary gland hypoplasia, 2 had pituitary stalk dysplasia (pituitary stalk was either attenuated or not visualized), 2 had absent corpus callosum and one had absent posterior pituitary high intensity signal. All patients were replaced with appropriate hormonal replacement therapy. Two male children had micropenis which responded to testosterone therapy. CONCLUSION: The syndrome of septo-optic dysplasia is commonly associated with hypothalamic hypopituitarism including anterior and posterior pituitary hormonal deficiencies. Early diagnosis of this syndrome is critical as the hormonal deficiencies can be life threatening.

Cytogenetics and etiology of ambiguous genitalia in 120 pediatric patients.

BACKGROUND: A newborn with ambiguous genitalia needs prompt evaluation to detect life-threatening conditions (e.g., salt-losing crisis in congenital adrenal hyperplasia [CAH]) and gender assignment. Sex assignment in these children continues to be a challenging diagnostic and therapeutic problem. We studied the causes and characteristics of ambiguous genitalia in children who were referred to a cytogenetic laboratory. PATIENTS AND METHODS: We retrospectively reviewed a total of 120 medical records of patients with a primary indication of ambiguous genitalia that were referred to the cytogenetic lab for karyotyping during the period of 1989 to 1999. Diagnosis was based on a clinical impression from the primary physician, who was primarily a staff pediatrician, endocrinologist and/or pediatric urologist. RESULTS: CAH was the underlying cause of ambiguous genitalia in 41 of 63 patients with ambiguity due to endocrine causes; 39 of these patients showed a 46,XX karyotype and 2 cases were 46,XY (both the 46,XY patients had 3 beta-hydroxylase deficiency). In 57 patients, ambiguous genitalia were due to congenital developmental defects. The most common endocrine case of ambiguous genitalia was 21-OH deficiency. Seven patients were classified as idiopathic with six showing the 46,XY and one the 46,XX karyotype. Gender was reassigned at birth or at diagnosis in 15 patients. CONCLUSION: The etiology of ambiguous genitalia is variable. The physician managing these families could minimize the trauma of having a child with unidentified sex by providing appropriate genetic counseling so that the parents can make an early decision. Prenatal DNA testing in at-risk families should be considered and appropriate therapy offered to minimize or prevent genital ambiguity.