LHX2 haploinsufficiency causes a variable neurodevelopmental disorder.

PURPOSE: LHX2 encodes the LIM homeobox 2 transcription factor (LHX2), which is highly expressed in brain and well conserved across species, but it has not been clearly linked to neurodevelopmental disorders (NDDs) to date. METHODS: Through international collaboration, we identified 19 individuals from 18 families with variable neurodevelopmental phenotypes, carrying a small chromosomal deletion, likely gene-disrupting or missense variants in LHX2. Functional consequences of missense variants were investigated in cellular systems. RESULTS: Affected individuals presented with developmental and/or behavioral abnormalities, autism spectrum disorder, variable intellectual disability, and microcephaly. We observed nucleolar accumulation for 2 missense variants located within the DNA-binding HOX domain, impaired interaction with co-factor LDB1 for another variant located in the protein-protein interaction-mediating LIM domain, and impaired transcriptional activation by luciferase assay for 4 missense variants. CONCLUSION: We implicate LHX2 haploinsufficiency by deletion and likely gene-disrupting variants as causative for a variable NDD. Our findings suggest a loss-of-function mechanism also for likely pathogenic LHX2 missense variants. Together, our observations underscore the importance of LHX2 in the nervous system and for variable neurodevelopmental phenotypes.

Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities.

PURPOSE: Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder. METHODS: We assembled a cohort of 51 affected individuals from 39 different families, gathering clinical information from 36 newly described affected individuals and reviewing data of 15 individuals from the literature. RESULTS: The main clinical characteristics of the PRMT7-related syndrome are short stature, mild to severe developmental delay/intellectual disability, hypotonia, brachydactyly, and distinct facial morphology, including bifrontal narrowing, prominent supraorbital ridges, sparse eyebrows, short nose with full/broad nasal tip, thin upper lip, full and everted lower lip, and a prominent or squared-off jaw. Additional variable findings include seizures, obesity, nonspecific magnetic resonance imaging abnormalities, eye abnormalities (i.e., strabismus or nystagmus), and hearing loss. CONCLUSION: This study further delineates and expands the molecular, phenotypic spectrum and natural history of PRMT7-related syndrome characterized by a neurodevelopmental disorder with skeletal, growth, and endocrine abnormalities.

Inherited and de novo variants extend the etiology of TAOK1-associated neurodevelopmental disorder.

Alterations in the TAOK1 gene have recently emerged as the cause of developmental delay with or without intellectual impairment or behavioral abnormalities (MIM # 619575). The 32 cases currently described in the literature have predominantly de novo alterations in TAOK1 and a wide spectrum of neurodevelopmental abnormalities. Here, we report four patients with novel pathogenic TAOK1 variants identified by research genome sequencing, clinical exome sequencing, and international matchmaking. The overlapping clinical features of our patients are consistent with the emerging core phenotype of TAOK1-associated syndrome: facial dysmorphism, feeding difficulties, global developmental delay, joint laxity, and hypotonia. However, behavioral abnormalities and gastrointestinal issues are more common in our cohort than previously reported. Two patients have de novo TAOK1 variants (one missense, one splice site) consistent with most known alterations in this gene. However, we also report the first sibling pair who both inherited a TAOK1 frameshift variant from a mildly affected mother. Our findings suggest that incomplete penetrance and variable expressivity are relatively common in TAOK1-associated syndrome, which holds important implications for clinical genetic testing.

Lack of Catch-Up Growth with Growth Hormone Treatment in a Child Born Small for Gestational Age Leading to a Diagnosis of Noonan Syndrome with a Pathogenic PTPN11 Variant.

BACKGROUND: Growth hormone (GH) treatment increases the adult height of short children born small for gestational age (SGA). Catch-up growth is associated with a younger age, shorter height, and prepubertal status at the onset of GH treatment. We report a 12 11/12-year-old girl born SGA who received GH for 5 years without catch-up growth and was diagnosed with Noonan Syndrome (NS). RESULTS: A 5-year-and-9-month-old 46, XX girl born SGA was started on GH treatment at a dose of 0.32 mg/kg/week. Her midparental target height is 158.6 cm. Endocrine work up showed an IGF-1 level 69 ng/ml (Normal (N): 55-238 ng/ml), IGFBP3 2.6 mg/L (N: 1.9-5.2 mg/L), TSH 3.2 mIU/L (N: 0.35-5.5 mIU/L), and a normal skeletal survey. Height was 96 cm (0.1%; Ht SDS -2.9), weight 14 kgs (1%; Wt SDS -2.3), and Tanner 1 breast and pubic hair were observed. Due to the poor catch-up growth on GH treatment, she was referred to Genetics to elucidate genetic or syndromic causes of short stature. She was noted to have posteriorly rotated ears and slight down slanting of the palpebral fissures. Genetic findings showed a heterozygous pathogenic variant in PTPN11 (c.922A > G (p.Asn308Asp)) diagnostic for NS. This finding is de novo given negative parental testing. She was noted to have a heterozygous missense variant of unknown significance (VUS) in FGFR3: c.746C > A (p.Ser249Tyr). FGFR3 is associated with multiple skeletal dysplasias including thanatophoric dysplasia, achondroplasia, and Crouzon syndrome and hypochondroplasia. Clinical correlation is poor for these syndromes. CONCLUSION: Diminished catch-up growth and response to GH treatment in a child born SGA led to the diagnosis of NS. The concomitant diagnosis of SGA and NS may have affected the responsiveness of this child to the growth promoting effect of GH treatment.

EARLY-ONSET GONADOBLASTOMA IN A 13-MONTH-OLD INFANT WITH 46,XY COMPLETE GONADAL DYSGENESIS IDENTIFIED WITH PRENATAL TESTING: A CASE OF CHROMOSOME 9p DELETION.

OBJECTIVE: Individuals with 46,XY complete gonadal dysgenesis (CGD) are at high risk of developing gonadal neoplasms. Chromosome 9p monosomy with deletion of the DMRT1 gene, a key transcription factor in testicular development, is one of the known causes of 46,XY CGD. Noninvasive prenatal testing (NIPT) is being increasingly used, and can identify disorders of sexual development (DSDs). METHODS: We report the case of a 46,XY infant with phenotypically female external genitalia, müllerian structures including uterus and fallopian tubes, and bilateral streak gonads who was found to have unilateral gonadoblastoma at 13 months. 46,XY DSD was suggested prenatally when discordance between NIPT and fetal ultrasound was noted. RESULTS: Genetic investigation revealed a deletion of 12.5 million base pairs at chromosome 9p24.3, which includes the doublesex and MAB-3-related transcription factor-1 (DMRT1) gene. CONCLUSION: Current guidelines recommend gonadectomy at the time of diagnosis in cases of 46,XY CGD, and our patient had gonadoblastoma at 13 months. 46,XY DSD, including rare disorders such as CGD, will be increasingly identified before birth with more widespread use of NIPT, raising the question about the appropriate timing of gonadectomy in prenatal diagnoses. Our case supports the current recommendation to perform gonadectomy as early as possible after diagnosis.

Hypogonadotropic Hypogonadism and Kleefstra Syndrome due to a Pathogenic Variant in the EHMT1 Gene: An Underrecognized Association.

Kleefstra syndrome is a genetic condition characterized by intellectual disability, childhood hypotonia, and facial dysmorphisms. Genital anomalies such as micropenis, cryptorchidism, and hypospadias have been reported in 30-40% of males diagnosed with the disease. However, endocrinological investigations have been limited. We describe a case of an adolescent male with Kleefstra syndrome due to a pathogenic variant in the EHMT1 gene whose workup for isolated micropenis is suggestive of a partial hypogonadotropic hypogonadism. A possible endocrine mechanism of the genital anomaly associated with Kleefstra syndrome is discussed.

Impact of Co-management at the Primary-Subspecialty Care Interface on Follow-up and Referral Patterns for Patients With Concussion.

BACKGROUND: Co-management is a collaborative care model that consists of structured tools to define and document care delivered by 2 or more providers. We evaluated the impact of implementing co-management at the interface between pediatric primary care providers (PCPs) and subspecialists. METHODS: Participating PCPs (n = 9) were trained on management of concussion using the co-management tools. Co-managed patients with concussion were prospectively enrolled (n = 148) and compared to a retrospective audit of non-co-managed patients (n = 50). RESULTS: PCPs using co-management demonstrated adherence to the tools. PCPs were significantly more likely to provide follow-up care to patients when using the co-management tools. All participating PCPs reported that co-management enhanced their expertise in caring for patients with concussion. CONCLUSIONS: Co-management can enhance PCPs' capacity to independently manage the care of patients with concussion. Co-management led to an observed change in practice that merits further exploration in terms of cost, quality, and clinical outcomes.

Survey of insulin site rotation in youth with type 1 diabetes mellitus.

OBJECTIVE: Injection site rotation is an important component of insulin administration and is helpful in preventing lipodystrophy in type 1 diabetes (T1DM). We examined the number of injection/infusion sites (sites) used by youth with T1DM and their perceived barriers to using new sites for insulin. METHODS: Two hundred and one youth with T1DM completed a 24-item survey about site rotation practices and barriers to site rotation during a routine diabetes appointment. RESULTS: Fifteen percent of youth reported using at least four distinct sites in their rotation plan, while 22% reported using only one site. A negative correlation was found between number of sites used and the number of perceived barriers endorsed by youth on multiple daily injections. Fear of pain was the most common barrier endorsed by youth. CONCLUSION: Many youth with T1DM may not adhere to an adequate site rotation plan. Regular assessment of insulin sites and counseling regarding adequate site rotation is needed when managing diabetes in youth. Relaxation and distraction may help to reduce youths' fear of pain when rotating to new insulin sites.

Illinois trauma centers and intimate partner violence: are we doing our share?

Intimate partner violence (IPV) is a major source of morbidity and mortality nationally. Trauma Centers can be very helpful for victims of IPV but there may be variability in IPV resource provision. A survey was mailed to each of the 65 Trauma Centers in Illinois. Stata and EZ-Text statistical software were used for analysis. Eighty-three percent of trauma centers returned the survey. Ninety percent of respondents had an IPV screening policy. All but one Center reported having IPV services available, including social work (93%) and 24 hour/day IPV teams (7%). Most Centers felt their IPV services were adequate (69%), but 22% felt services were inadequate, particularly resource availability. Trauma Centers in the state of Illinois are generally succeeding at screening for IPV. However, there is lack of uniformity with respect to screening and services, suggesting that there is room for improvement.