Expanding the Phenotypic Spectrum of Kenny-Caffey Syndrome.

CONTEXT: Kenny-Caffey syndrome (KCS) is a rare hereditary disorder characterized by short stature, hypoparathyroidism, and electrolyte disturbances. KCS1 and KCS2 are caused by pathogenic variants in TBCE and FAM111A, respectively. Clinically the phenotypes are difficult to distinguish. OBJECTIVE: The objective was to determine and expand the phenotypic spectrum of KCS1 and KCS2 in order to anticipate complications that may arise in these disorders. METHODS: We clinically and genetically analyzed 10 KCS2 patients from 7 families. Because we found unusual phenotypes in our cohort, we performed a systematic review of genetically confirmed KCS cases using PubMed and Scopus. Evaluation by 3 researchers led to the inclusion of 26 papers for KCS1 and 16 for KCS2, totaling 205 patients. Data were extracted following the Cochrane guidelines and assessed by 2 independent researchers. RESULTS: Several patients in our KCS2 cohort presented with intellectual disability (3/10) and chronic kidney disease (6/10), which are not considered common findings in KCS2. Systematic review of all reported KCS cases showed that the phenotypes of KCS1 and KCS2 overlap for postnatal growth retardation (KCS1: 52/52, KCS2: 23/23), low parathyroid hormone levels (121/121, 16/20), electrolyte disturbances (139/139, 24/27), dental abnormalities (47/50, 15/16), ocular abnormalities (57/60, 22/23), and seizures/spasms (103/115, 13/16). Symptoms more prevalent in KCS1 included intellectual disability (74/80, 5/24), whereas in KCS2 bone cortical thickening (1/18, 16/20) and medullary stenosis (7/46, 27/28) were more common. CONCLUSION: Our case series established chronic kidney disease as a new feature of KCS2. In the literature, we found substantial overlap in the phenotypic spectra of KCS1 and KCS2, but identified intellectual disability and the abnormal bone phenotype as the most distinguishing features.

Withdrawn as duplicate: Expanding the phenotypic spectrum of Kenny-Caffey syndrome: a case series and systematic literature review.

This article has been withdrawn due to a publisher error that caused it to be duplicated. The definitive version of this article is published under https://doi.org/10.1210/clinem/dgad147.

Setmelanotide: a promising advancement for pediatric patients with rare forms of genetic obesity.

PURPOSE OF REVIEW: Examine Setmelanotide use in patients with rare genetic variants that disrupt the melanocortin pathway. RECENT FINDINGS: Between February 2017 and September 2018, 10 participants with pro-opiomelanocortin (POMC)/ proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency and 11 participants with leptin receptor (LEPR) deficiency were enrolled in open-label, phase 3 trials at 10 centers in the United States and internationally to assess the efficacy and safety of the melanocortin-4 receptor (MC4R) agonist Setmelanotide. 80% of POMC participants and 45% of LEPR participants achieved at least 10% weight loss at 1 year. Significant changes in hunger scores were seen for both cohorts as well. Setmelanotide was well tolerated with injection site reactions and hyperpigmentation being the most common adverse events reported. As a result, Setmelanotide was approved by the U.S. FDA in 2020 for chronic weight management in adult and pediatric patients ≥6 years of age with POMC, LEPR, or PCSK1 deficiency. In 2022, its approval was extended to include patients with Bardet-Biedel syndrome (BBS) after phase 3 trial data showed that, on average, Setmelanotide treatment resulted in a BMI loss of 7.9% for the 44 BBS participants. SUMMARY: Rare genetic variants such as POMC, LEPR, and PCSK1 deficiency disrupt MC4R pathway signaling, resulting in severe early-onset obesity, hyperphagia, and increased risk for metabolic co-morbidities. Patients with BBS also demonstrate severe early-onset obesity and hyperphagia, due in part to defective MC4R signaling. Setmelanotide has shown promising benefits in improving satiety scores and weight-related outcomes in patients with these early-life genetic obesity conditions, although longer-term studies are needed.

The relationship between dietary patterns, body mass index percentile, and household food security in young urban children.

BACKGROUND: The relationship between food insecurity and child obesity is unclear. Few studies have examined dietary patterns in children with regard to household food security and weight status. The aim of this study was to examine the association between household food security, dietary intake, and BMI percentile in low-income, preschool children. METHODS: Low-income caregivers (n=222) with children ages 2-4 years were enrolled in a primary-care-based obesity prevention/reversal study (Steps to Growing Up Healthy) between October 2010 and December 2011. At baseline, demographic data, household food security status (US Household Food Security Instrument) and dietary intake (Children's Dietary Questionnaire; CDQ) were collected. BMI percentile was calculated from anthropometric data. RESULTS: Participating children were primarily Hispanic (90%), Medicaid insured (95%), 50% female, 35±8.7 months of age (mean±standard deviation), 19% overweight (BMI 85th-94th percentile), and 29% obese (≥95th percentile). Thirty-eight percent of interviews were conducted in Spanish. Twenty-five percent of households reported food insecurity. There was no association between household food insecurity and child BMI percentile. Dietary patterns of the children based on the CDQ did not differ by household food security status. Food group subscale scores (fruit and vegetable, fat from dairy, sweetened beverages, and noncore foods) on the CDQ did not differ between normal weight and overweight/obese children. Maternal depression and stress did not mediate the relationship between household food insecurity and child weight status. Hispanic children were more likely to be overweight or obese in both food-secure and food-insecure households. CONCLUSIONS: Household food insecurity was not associated with child BMI percentile in this study. Dietary intake patterns of children from food-insecure households were not different compared to those from food-secure households.

Pediatric pulmonary arterial hypertension and hyperthyroidism: a potentially fatal combination.

CONTEXT: Patients with pulmonary arterial hypertension (PAH) who develop hyperthyroidism are at risk for acute cardiopulmonary decompensation and death. CASES AND SETTING: We present a series of eight idiopathic PAH/heritable PAH pediatric patients who developed hyperthyroidism between 1999 and 2011. Institutional Review Board approval was obtained; informed consent was waived due to the retrospective nature of the series. All eight patients were receiving iv epoprostenol; five of the eight patients presented with acute cardiopulmonary decompensation in the setting of hyperthyroidism. In the remaining three patients, hyperthyroidism was detected during routine screening of thyroid function tests. The one patient who underwent emergency thyroidectomy was the only survivor of those who presented in cardiopulmonary decline. EVIDENCE SYNTHESIS: Aggressive treatment of the hyperthyroid state, including emergency total thyroidectomy and escalation of targeted PAH therapy and ß-blockade when warranted, may prove lifesaving in these patients. Prompt thyroidectomy or radioactive iodine ablation should be considered for clinically stable PAH patients with early and/or mild hyperthyroidism to avoid potentially life-threatening cardiopulmonary decompensation. CONCLUSIONS: Although the association between hyperthyroidism and PAH remains poorly understood, the potential impact of hyperthyroidism on the cardiopulmonary status of PAH patients must not be ignored. Hyperthyroidism must be identified early in this patient population to optimize intervention before acute decompensation. Thyroid function tests should be checked routinely in patients with PAH, particularly those on iv epoprostenol, and urgently in patients with acute decompensation or symptoms of hyperthyroidism.

Recommendations for treatment of nonclassic congenital adrenal hyperplasia (NCCAH): an update.

Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders. 21-Hydroxylase deficiency, in which there are mutations in CYP21A2 (the gene encoding the adrenal 21-hydroxylase enzyme), is the most common form (90%) of CAH. In classic CAH there is impaired cortisol production with diagnostic increased levels of 17-OH progesterone. Excess androgen production results in virilization and in the newborn female may cause development of ambiguous external genitalia. Three-fourths of patients with classic CAH also have aldosterone insufficiency, which can result in salt-wasting; in infancy this manifests as shock, hyponatremia and hyperkalemia. CAH has a reported incidence of 1:10,000-1:20,000 births although there is an increased prevalence in certain ethnic groups. Nonclassic CAH (NCCAH) is a less severe form of the disorder, in which there is 20-50% of 21-hydroxylase enzyme activity (vs. 0-5% in classic CAH) and no salt wasting. The degree of symptoms related to androgen excess is variable and may be progressive with age, although some individuals are asymptomatic. NCCAH has an incidence of 1:1000-1:2000 births (0.1-0.2% prevalence) in the White population; an even higher prevalence is noted in certain ethnic groups such as Ashkenazi Jews (1-2%). As many as two-thirds of persons with NCCAH are compound heterozygotes and carry a severe and mild mutation on different alleles. This paper discusses the genetics of NCCAH, along with its variable phenotypic expression, and reviews the clinical course in untreated patients, which includes rapid early childhood growth, advanced skeletal age, premature adrenarche, acne, impaired reproductive function in both sexes and hirsutism as well as menstrual disorders in females. Finally, it addresses treatment with glucocorticoids vs. non treatment and other therapies, particularly with respect to long term issues such as adult metabolic disease including insulin resistance, cardiovascular disease, metabolic syndrome, and bone mineral density.

Congenital adrenal hyperplasia: an update in children.

PURPOSE OF REVIEW: Congenital adrenal hyperplasia (CAH) in children, the majority of which is due to 21-hydroxylase deficiency, represents a group of disorders in which there is impaired cortisol synthesis and abnormalities in adrenal hormonal profiles. There continues to be debate regarding the optimal management of and treatment for these children. This review will highlight the most recent advances in neonatal screening for CAH, as well as the timeliest recommendations for the treatment and management of 21-hydroxylase deficiency, both the classic and nonclassic forms of the disorder. RECENT FINDINGS: Substantive advancements have been made with regard to neonatal screening for CAH, allowing for earlier diagnosis, while minimizing the morbidity and mortality associated with delayed detection. Although the achievement of normal growth and development remains the ultimate goal of treatment, recent studies have provided further insight into the management and refinement of therapy in these children. SUMMARY: The optimal management and treatment for children with CAH is still unclear. Although there have been recent advances in the diagnosis and treatment of this group of disorders, there is still much to learn in order to optimize therapy for these individuals.

Septic arthritis secondary to fusobacterium necrophorum in a 4-year-old girl: case report and review of the literature.

We report an unusual case of septic arthritis in a 4-year-old child caused by Fusobacterium necrophorum. In spite of aggressive parenteral antibiotic therapy with ampicillin-sulbactam after surgical drainage, disease recurred, requiring additional arthrotomies. The infection was eventually eradicated with parenteral meropenem and clindamycin, and additional surgical drainage.