De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders.

Recurrent somatic variants in SPOP are cancer specific; endometrial and prostate cancers result from gain-of-function and dominant-negative effects toward BET proteins, respectively. By using clinical exome sequencing, we identified six de novo pathogenic missense variants in SPOP in seven individuals with developmental delay and/or intellectual disability, facial dysmorphisms, and congenital anomalies. Two individuals shared craniofacial dysmorphisms, including congenital microcephaly, that were strikingly different from those of the other five individuals, who had (relative) macrocephaly and hypertelorism. We measured the effect of SPOP variants on BET protein amounts in human Ishikawa endometrial cancer cells and patient-derived cell lines because we hypothesized that variants would lead to functional divergent effects on BET proteins. The de novo variants c.362G>A (p.Arg121Gln) and c. 430G>A (p.Asp144Asn), identified in the first two individuals, resulted in a gain of function, and conversely, the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T (p.Gly132Val), and c.412C>T (p.Arg138Cys) variants resulted in a dominant-negative effect. Our findings suggest that these opposite functional effects caused by the variants in SPOP result in two distinct and clinically recognizable syndromic forms of intellectual disability with contrasting craniofacial dysmorphisms.

Promoting Healthy Sexuality for Children and Adolescents With Disabilities.

This clinical report updates a 2006 report from the American Academy of Pediatrics titled "Sexuality of Children and Adolescents With Developmental Disabilities." The development of a healthy sexuality best occurs through appropriate education, absence of coercion and violence, and developmental acquisition of skills to navigate feelings, desires, relationships, and social pressures. Pediatric health care providers are important resources for anticipatory guidance and education for all children and youth as they understand their changing bodies, feelings, and behaviors. Yet, youth with disabilities and their families report inadequate education and guidance from pediatricians regarding sexual health development. In the decade since the original clinical report was published, there have been many advancements in the understanding and care of children and youth with disabilities, in part because of an increased prevalence and breadth of autism spectrum disorder as well as an increased longevity of individuals with medically complex and severely disabling conditions. During this same time frame, sexual education in US public schools has diminished, and there is emerging evidence that the attitudes and beliefs of all youth (with and without disability) about sex and sexuality are being formed through media rather than formal education or parent and/or health care provider sources. This report aims to provide the pediatric health care provider with resources and tools for clinical practice to address the sexual development of children and youth with disabilities. The report emphasizes strategies to promote competence in achieving a healthy sexuality regardless of physical, cognitive, or socioemotional limitations.

Nonoral feeding for children and youth with developmental or acquired disabilities.

The decision to initiate enteral feedings is multifaceted, involving medical, financial, cultural, and emotional considerations. Children who have developmental or acquired disabilities are at risk for having primary and secondary conditions that affect growth and nutritional well-being. This clinical report provides (1) an overview of clinical issues in children who have developmental or acquired disabilities that may prompt a need to consider nonoral feedings, (2) a systematic way to support the child and family in clinical decisions related to initiating nonoral feeding, (3) information on surgical options that the family may need to consider in that decision-making process, and (4) pediatric guidance for ongoing care after initiation of nonoral feeding intervention, including care of the gastrostomy tube and skin site. Ongoing medical and psychosocial support is needed after initiation of nonoral feedings and is best provided through the collaborative efforts of the family and a team of professionals that may include the pediatrician, dietitian, social worker, and/or therapists.

Home care of children and youth with complex health care needs and technology dependencies.

Children and youth with complex medical issues, especially those with technology dependencies, experience frequent and often lengthy hospitalizations. Hospital discharges for these children can be a complicated process that requires a deliberate, multistep approach. In addition to successful discharges to home, it is essential that pediatric providers develop and implement an interdisciplinary and coordinated plan of care that addresses the child's ongoing health care needs. The goal is to ensure that each child remains healthy, thrives, and obtains optimal medical home and developmental supports that promote ongoing care at home and minimize recurrent hospitalizations. This clinical report presents an approach to discharging the child with complex medical needs with technology dependencies from hospital to home and then continually addressing the needs of the child and family in the home environment.

Autistic spectrum disorder in a 9-year-old girl with macrocephaly.

CASE: A 9-year-old girl was brought for consultation due to autism and a large head circumference. Her birth weight was 6 pounds after a 37-week gestation to a healthy G3P1SAb 2 mother. She had been a healthy child with the exception of the development of a lipomatous lesion on the left thigh, requiring surgical removal at age 3(1/2) years. Autism was diagnosed at age 5 yr by a developmental pediatrician. She did not have cognitive disabilities or a history of seizures. The family history was notable for maternal infertility with no history of developmental disabilities, large body or head size, or malignancy in close relatives.On physical examination, she was a mildly obese girl with a large head. Her weight was 50.4 kg (>95%), height was 142 cm (90%), and head circumference was 60.3 cm (significantly >95%; 4SDs above the mean). Examination of her skin was notable for a 2 x 6 cm scar on her left thigh and three café au lait macules on her trunk. She was Tanner Stage I. Mild hypotonia with normal deep tendon reflexes was observed; the remainder of the neurological examination was normal.Laboratory studies included high-resolution chromosomes, fragile X, metabolic screens, and methylation for Prader Willie Syndrome and Angelman Syndrome; all these studies were normal. Molecular testing of the PTEN gene (phosphatase and tensin homolog protein) revealed a R355X mutation, consistent with the diagnosis of Bannayan-Riley-Ruvalcaba Syndrome (BRRS). In parents and siblings, PTEN test results were negative for mutations.Endocrine evaluation revealed an abnormal thyroid nodule on ultrasound. Computed tomography and positron emission tomography scans raised suspicion of malignancy. She underwent a total thyroidectomy; the pathology report revealed a thyroid adenoma with Hurthle cells. She was treated with thyroid hormone replacement therapy.

Sexuality of children and adolescents with developmental disabilities.

Children and adolescents with developmental disabilities, like all children, are sexual persons. However, attention to their complex medical and functional issues often consumes time that might otherwise be invested in addressing the anatomic, physiologic, emotional, and social aspects of their developing sexuality. This report discusses issues of puberty, contraception, psychosexual development, sexual abuse, and sexuality education specific to children and adolescents with disabilities and their families. Pediatricians, in the context of the medical home, are encouraged to discuss issues of sexuality on a regular basis, ensure the privacy of each child and adolescent, promote self-care and social independence among persons with disabilities, advocate for appropriate sexuality education, and provide ongoing education for children and adolescents with developmental disabilities and their families.