Submucous cleft palate (SMCP) is a unique type of cleft palate. Delayed diagnosis is frequently associated with suboptimal speech outcomes. Early detection of SMCP has thus emerged as a key priority in mitigating this challenge. This study aims to identify early diagnostic indicators of SMCP by analysing the association between chief complaints and age, along with early symptoms reported by caregivers before the onset of speech problems. Medical records of 278 consecutive SMCP outpatients were retrospectively reviewed between January 1, 2013 and September 30, 2023. Three clinical manifestations related to SMCP were identified in medical records: speech problems, abnormal palatal morphology, and feeding difficulties. Descriptive statistical analyses were performed to evaluate the distribution of chief complaints across different age groups and the percentage of feeding difficulties and abnormal palatal morphology in the subgroup with speech problems as the chief complaint. Regarding the chief complaint, speech problem was the most common chief complaint for consultation (183 patients, 65.8%), followed by abnormal palatal morphology (88 patients, 31.7%), and 7 (2.5%) patients reporting feeding difficulties as the chief complaint. Abnormal palatal morphology emerged as the most common chief complaint in patients younger than 2 years (47 patients, 92.2%). In contrast, the number of patients reporting speech problems as the chief complaint increased significantly in patients older than 2 years (183 patients, 80.6%). Speech problem was identified as the most frequent reason for consultation among patients with SMCP. Feeding difficulties, including nasal regurgitation, were among the earlier diagnostic indicators for SMCP.

SATB2-associated syndrome (SAS) results from various mutations of the SATB2 gene and associates a neurodevelopmental disorder including major speech delay, intellectual disability, and behavioral problems with dental anomalies, sometimes a cleft palate, risk of osteoporosis, and facial dysmorphism. The principal objective of this study was to describe the oral phenotype of young children with SATB2-associated syndrome, especially in terms of orofacial malformation of Robin Sequence (RS) spectrum (bifid uvula, cleft palate, or RS, dental malformation, feeding and communication, with data from a national cohort. The secondary objective was to determine whether feeding and communication disorders were more severe when associated with an orofacial malformation of RS spectrum. We conducted a retrospective cross-sectional study among the largest possible cohort of patients with a mutation of the SATB2 gene in France. A questionnaire completed by the referring physicians and by telephone with parents enabled us to collect the following clinical information: (1) orofacial morphology, feeding difficulties, and pharyngeal functioning from birth to 3 years, (2) communication and language from 0 to 6 years, (3) speech development at the last examination. The study included 40 patients. Early and persistent feeding difficulties were found in 55% of the children. Communication was abnormal from the first months of life, with poor babbling in 85% of them. A major language delay was described in all patients; 65% had a vocabulary of 10 words or less. An anomaly of RS spectrum was found in half the cases, and dental malformations were described in 90%. Feeding difficulties and language delay were greater in the group with one or more orofacial malformations than the group with none. This study confirmed the severity of oral involvement, affecting feeding and speech simultaneously, in individuals with SAS. It raises the question of why the oral phenotype involving feeding and speech is more severe in the presence of cleft palate or RS. We recommend close monitoring of prelanguage communication in infants with apparently isolated cleft palate or RS and the search for SATB2 impairment when a cleft palate or RS is found, especially in the prenatal period.

Inherited metabolic disorders (IMDs) are genetic disorders that occur in as many as 1:2500 births worldwide. Nevertheless, they are quite rare individually and even more rare is the co-occurrence of two IMDs in one individual. To better understand the metabolic cross-talk between glycosylation changes and deficient energy metabolism, and its potential effect on outcomes, we evaluated patient fibroblasts with likely pathogenic variants in PGM1 and pathogenic variants in NDUFA13 derived from a patient who passed away at 16 years of age. The patient presented with characteristic of PGM1-CDG including bifid uvula, muscle involvement, abnormal glycosylation in blood, and elevated liver transaminases. In addition, hearing loss, seizures, elevated plasma and CSF lactate and a Leigh-like MRI brain pattern were present, which are commonly associated with Leigh syndrome. PGM1-CDG has been reported in about 70 individuals, while NDUFA13 deficiency has so far only been reported in 13 patients. As abundant energy is essential for glycosylation, and both PGM1 and NDUFA13 are linked to energy metabolism, we sought to better understand the underlying biochemical cause of the patient's clinical presentation. To do so, we performed extensive investigations including tracer metabolomics, lipidomics and enzymatic studies on the patient's fibroblasts. We found a profound depletion of UDP-hexoses, consistent with PGM1-CDG. Complex I enzyme activity and mitochondrial function were also impaired, corroborating complex I deficiency and Leigh syndrome. Further, lipidomics analysis showed similarities with both PGM1-CDG and OXPHOS-deficient patients. Based on our results, the patient was diagnosed with both PGM1-CDG and Leigh syndrome. In summary, we present the first case of combined CDG and Leigh syndrome, caused by (likely) pathogenic variants in PGM1 and NDUFA13, and underline the importance of considering the synergistic effects of multiple disease-causing variants in patients with complex clinical presentation, leading to the patient's early demise. Individuals with 22q11.2 deletion syndrome (22q11.2DS) can present with a wide range of features that are highly variable, even within families. The major clinical manifestations of 22q11.2DS include congenital heart disease, particularly conotruncal malformations (ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus), palatal abnormalities (velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate), immune deficiency, characteristic facial features, and learning difficulties. Hearing loss can be sensorineural and/or conductive. Laryngotracheoesophageal, gastrointestinal, ophthalmologic, central nervous system, skeletal, and genitourinary anomalies also occur. Psychiatric illness and autoimmune disorders are more common in individuals with 22q11.2DS. The diagnosis of 22q11.2DS is established by identification of a heterozygous deletion at chromosome 22q11.2 on chromosomal microarray analysis or other genomic analyses. Treatment of manifestations: Cardiac anomalies are treated as recommended by cardiologist; surgical repair for palate anomalies as recommended by otolaryngologist; feeding issues are treated with modification of spoon placement; standard treatment for gastroesophageal reflux and gastrointestinal dysmotility; immune deficiency requires aggressive treatment of infections; rarely, prophylactic antibiotics, IVIG therapy, or thymus tissue implantation are required; irradiated blood products are recommended until normalization of the immune system can be confirmed; treatment of autoimmune disease as per immunologist; calcium supplementation and referral to an endocrinologist and nephrologist because of increased risk of renal calculi if long-term supplementation is required; standard treatment for growth hormone deficiency; standard treatment for ocular anomalies; hearing aids may be helpful for hearing loss; occupational, physical, and speech therapy with introduction of sign language by age one year, educational and behavioral therapy; support and treatment for psychiatric disease as indicated; activity restriction as recommended by an orthopedist for cervical spine anomalies; surgery and treatment as recommended by a nephrologist for renal anomalies; routine dental treatment with consideration of sealants. Surveillance: Evaluation for nasal speech quality after language emergence; antibody studies to assess seroconversion; reevaluate immune status in childhood before administration of live vaccines; annual complete blood count and differential; serum ionized calcium every three to six months in infancy, every five years through childhood, every one to two years thereafter, preoperatively and postoperatively, and regularly during pregnancy; TSH and free T4 annually; ophthalmologic evaluation between age one and three years or as indicated; audiology evaluation in infancy, at preschool age, and in school age children; developmental assessments annually; annual clinical surveillance for scoliosis; dental examination every six months. Agents/circumstances to avoid: Infants with lymphocyte abnormalities should not be immunized with live vaccines (e.g., oral polio, MMR). Carbonated drinks and alcohol consumption may exacerbate hypocalcemia. Caffeine intake may contribute to or worsen anxiety. 22q11.2DS is an autosomal dominant contiguous gene deletion syndrome. In 22q11.2DS caused by a 3.0 (2.54)-Mb deletion, the deletion is de novo in more than 90% of individuals and inherited from a heterozygous parent in about 10% of individuals. Sixty percent of individuals with 22q11.2DS caused by a nested 22q11.2 deletion inherited the deletion from an affected parent. Offspring of affected individuals have a 50% chance of inheriting the 22q11.2 deletion. Once the 22q11.2 deletion has been identified in an affected family member, prenatal testing using FISH, MLPA, or array studies for a pregnancy at increased risk and preimplantation genetic testing are possible.

The DOCK3 gene (NM_004947.5) is located on chromosome 3p21.2 spanning 53 exons and encodes the dedicator of cytokinesis 3 protein. DOCK3 belongs to the family of guanine nucleotide exchange factors (GEFs) that activate GTPases. DOCK3 is expressed almost exclusively in the central nervous system and has been shown to promote axonal outgrowth. Biallelic disruptions of DOCK3 are implicated in a neurodevelopmental disorder presenting with intellectual disability, hypotonia and ataxia (OMIM: 618292). We report a 9-year-old female with global developmental delay, moderate intellectual disability, wide-based and ataxic gait, hypotonia, benign nocturnal myoclonus, bifid uvula, moderate obstructive sleep apnea, and alternating esotropia. Prior to enrollment in the Undiagnosed Rare Disease Clinic (URDC), the patient's clinical exome testing was negative. The subsequent enrollment in URDC allowed further research investigations through whole genome sequencing (GS) that identified two compound heterozygous variants in the DOCK3 gene, ultimately yielding an unequivocal definitive molecular diagnosis.

In allergic patients with recurrent respiratory infections, the association of antibody deficiencies, both selective and specific to polysaccharide responses, has been described. Male, no significant family history. At age 5, presented with cervical and axillary lymphadenopathy; biopsy ruled out malignancy, followed by remission. At age 7, developed nasal symptoms and wheezing. Admitted to Allergy at age 9 and diagnosed with asthma and rhinitis, sensitized to dust mites and grass. Good response to immunotherapy in the first 2 years; during the third year, developed recurrent respiratory and gastrointestinal infections every 15 days. At age 13, further workup was decided. Physical Examination: Weight 69 kg, height 1.7 m, obstructive turbinates, central bifid uvula, grade I tonsils, no lymphadenopathy, cardiopulmonary system unremarkable. Studies: Hemoglobin 15.6 g/dL, Hematocrit 46%, WBC 4005/μL, Lymphocytes 1200/μL (20%), Eosinophils 210/μL (3.6%), Platelets 219,000/μL. Low IgA 23 mg/dL (45-236), low IgM 27 mg/dL (52-242), IgE 11.9 IU/mL (≤3100), normal IgG 1060 mg/dL (560-1760), reconfirmed. Flow cytometry normal with normal B lymphocytes. Pneumococcal polysaccharide vaccine challenge showed adequate response to only 4 serotypes (<50% response). Management: Temporary treatment with prophylactic antibiotics and immunostimulants, with improvement in infectious episodes. Currently off prophylaxis. Discussion: Adolescent with quantitative IgA and IgM deficiency, currently normal IgG levels but impaired response to polysaccharide vaccine. Maintained under immunological surveillance due to potential progression to common variable immunodeficiency. Recurrent or invasive infections in treated asthma patients warrant investigation for antibody deficiency. En pacientes alérgicos con infecciones respiratorias recurrentes se ha descrito la asociación de deficiencia de anticuerpos, tanto selectivas como de respuesta a polisacáridos. Hombre, sin antecedentes familiares de importancia, a los 5 años adenopatías cervicales y axilares con biopsia que descartó malignidad, con posterior remisión. A los 7 años síntomas nasales y sibilancias, ingresa a Alergia a los 9 años y se diganosticó asma y rinitis, sensibilizado a ácaro y pasto. Buena respuesta a inmunoterapia primeros 2 años, el tercer año inicia con infecciones respiratorias y digestivas recurrentes hasta cada 15 días. A los 13 años se decide extensión de estudios. Exploración física: peso 69kg, talla 1.7m, cornnetes obstructivos, úvula central, bífida, amígdalas GI, sin adenopatías, cardiopulmonar sin alteraciones. Estudios: Hemoglobina 15.6, Hematocrito 46%, Leucocitos 4005, Linfocitos 1200 (20%), Eosinófilos 210 (3.6%), plaquetas 219000, IgA 23 baja(45-236), IgM 27 baja(52-242), IgE 11.9(3.100UI), IgG 1060 normal(560-1760) corroboradas. Citometría de flujo normal y linfocitos B normales. Se realiza prueba de polisacáridos antineumocócica solo con buena respuesta a 4 serotipos, <50% de respuesta. Se dio manejo temporal con antibiótico profiláctico más inmunoestimulantes con mejoría de procesos infecciosos. Actualmente sin profilaxis. Discusión: Adolescente con defecto cuantitativo de IgA e IgM y al momento con niveles normales de IgG con respuesta alterada a vacuna de polisacáridos, se mantiene en vigilancia inmunológica ante la posibilidad de presentar inmunodeficiencia comun variable. Las infecciones recurrentes o invasivas en pacientes ya tratados con asma amerita abordaje para defecto de anticuerpos. Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is characterized by developmental delay and intellectual disability. Behavioral issues and seizures are reported in more than half of affected individuals. Characteristic facial features include facial asymmetry, prominent forehead, horizontal eyebrows, ptosis, downslanted palpebral fissures, epicanthal folds, deep-set eyes, midface retrusion, depressed or other abnormality of the nasal bridge, low-set ears that may be posteriorly rotated, short and/or smooth philtrum, thin vermilion of the upper lip, bifid uvula, and high palate. Skeletal and ocular abnormalities, short stature, and genitourinary and kidney manifestations are common. Hematologic, cardiac, immune, gastrointestinal, and hearing abnormalities have also been reported. The diagnosis of ZTTK syndrome is established in a proband with characteristic features and a heterozygous pathogenic variant in SON identified by molecular genetic testing. Treatment of manifestations: None of the treatments available directly address SON deficiency. Supportive measures include developmental and educational support; standard treatment for seizures and movement disorder; treatment of craniosynostosis per craniofacial team; treatment of musculoskeletal manifestations per orthopedist; treatment of refractive errors and strabismus per ophthalmologist; low vision services as needed; nutritional support for feeding issues; treatment of growth hormone deficiency per endocrinologist; treatment of genitourinary and kidney manifestations per nephrologist and/or urologist; treatment of hematologic disorders per hematologist; surgical and/or medical treatment for cardiac anomalies; treat infections aggressively; in those with immune deficiency irradiated blood products are recommended; standard treatment of recurrent otitis media; management of bowel dysfunction and other gastrointestinal issues per gastroenterologist; hearing aids may be helpful; family and social work support. Surveillance: Assess developmental progress, educational needs, behavioral issues, neurologic manifestations, musculoskeletal evaluation, growth, nutrition, gastrointestinal and hematologic issues, and for recurrent infections at each visit; ophthalmologic evaluation per ophthalmologist; endocrine evaluation in those with growth hormone deficiency; kidney ultrasound annually or as needed; audiology evaluation annually; assess family and social work needs at each visit. ZTTK syndrome is an autosomal dominant disorder. Almost all probands reported to date with ZTTK syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a de novo SON pathogenic variant. Each child of an individual with ZTTK syndrome has a 50% chance of inheriting the SON pathogenic variant (data on reproduction in affected individuals are currently lacking, as most reported individuals are not yet of reproductive age). Once the SON pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.