Abstract This chapter provides pictures and clinical details of O-GlcNAc Transferase Deficiency, an XLID with craniofacial features (dolichocephaly and frontal hair upsweep), ocular findings, hearing loss, and behavioral manifestations. Alterations in OGT are responsible for this congenital disorder of glycosylation. The majority of cases have low birth weight and short stature. Microcephaly is less frequent. Development is globally delayed and cognitive function impaired. Seizures are uncommon among the reported cases. Abnormal vision and hearing loss are frequent. Behavioral problems occur in the majority of cases. Thin corpus callosum, periventricular leukomalacia, cerebral atrophy, and mega cisterna magna have been demonstrated in some cases.

Abstract This chapter provides pictures and clinical details of Waisman-Laxova syndrome, an XLID with macrocephaly, strabismus, parkinsonian rigidity and tremors, and seizures. The responsible gene, RAB39B, was identified in 2014. Although normal at birth, the head circumference increases thereafter and generally exceeds the 98th centile throughout childhood and adult life. Frontal prominence accompanies the macrocephaly. Otherwise, the craniofacial appearance is not distinctive, although high palate and crowded teeth occur in most and protruding ears in some. All developmental milestones are moderately delayed. Neurological signs dominate the phenotype. A general paucity of movement, tremors of the trunk and limbs, choreoathetoid movements, persistence of frontal lobe reflexes, cogwheel rigidity of the upper limbs, slow and shuffling gait, stooped posture, and hypokinetic dysarthria occur in most affected males. Seizures occur less often.

Abstract XLID with infantile onset choreoathetosis. The responsible gene, HSD17B10, encodes an hydroxyacyl-CoA-dehydrogenase.

Abstract This chapter provides pictures and clinical details of Kang syndrome, an XLID with microcephaly, frontal prominence, telecanthus, downturned mouth, short broad hands with brachydactyly, agenesis of corpus callosum, and spastic diplegia. The gene has not been localized. The face appears broad with frontal prominence, telecanthus, small nose with anteverted nares, and downturned mouth. Microcephaly or hydrocephaly occurs with malformations of the brain (agenesis of corpus callosum, interhemispheric cysts, gyral dysplasia, and lateral displacement of the ventricles). One case had unilateral cataract. The hands are short and broad, with short fingers and single flexion creases on the fifth fingers. The genitalia appear normal. Spastic diplegia ensues.

Abstract Assignment of XLID syndrome status is tentative, based on the clinical report of two brothers with short stature, small hands and feet with digital contractures, osteoporosis, obesity, and genital anomalies. Both had low birth weight at term gestation, upslanting palpebral fissures, lateral extension of the eyebrows, tented upper lip, abnormalities of eye movement, wormian bones in the lambdoid sutures, small hands and feet with wasting of the intrinsic muscles and finger contractures, narrow iliac wings, osteoporosis, and fractures with inadequate provocation. The body acquired eunuchoid shape and truncal obesity. At age 20 years, the older brother had moderate facial, axillary, and body hair; small penis; and large testes (4.5 x 5 cm). The younger brother had small penis, scant pubic hair, and undescended testes. A causative gene has not been identified nor mapped.

Abstract This chapter provides clinical details of GABRA3-Related XLID Seizures, an XLID with multiple forms of epilepsy that are often early onset in life and drug-resistant. Craniofacial findings include micrognathia, cleft palate, and nystagmus in some affected individuals. X-linked inheritance is demonstrated in some, but not all, families. Both males and females may be affected, and intrafamilial phenotypic variability has been observed. Pathogenic missense variants and an intragenic microduplication in gamma-aminobutyric acid receptor alpha-3 gene, GABRA3, resulting in reduced or loss of receptor function have been documented. Most patients have some dysmorphic features. Micrognathia, small mouth, high-arched or cleft palate, and nystagmus are commonly observed.

Abstract This chapter provides pictures and clinical details of Myotubular Myopathy, an XLID associated with hypotonia, weakness, and absent deep tendon reflexes secondary to myotubular myopathy. Truncating mutations in Myotubularin cause a severe phenotype, and missense mutations may be associated with milder forms. A craniofacial phenotype, resulting in large measure from hypotonia, may be recognized. Ptosis, arched upper lip, high palate, open mouth, thick alae nasi, and auricular helices accent an elongated and immobile face. The head tends to be large and elongated in its anteroposterior diameter. Hydrocephalus has been demonstrated in patients with intracranial hemorrhage in the perinatal period and in patients without this complication. Long slender digits are typical, contractures may be present, and cryptorchidism is commonly noted. The limbs are thin with decreased muscle mass.

Abstract This chapter provides clinical details of XLID-Ataxia-Seizures, an XLID with ataxia, seizures, and autism. Deletions and truncating variants in IL1RAPL2 have been found.

Abstract This chapter provides clinical details of ATP6AP2 Congenital Disorder of Glycosylation, an XLID with liver failure, immunodeficiency, and cutis laxa. The responsible gene, ATP6AP2, encodes an accessory subunit of the multi-subunit vacuolar-type H+-ATPase (V-ATPase). This protein is also referred to as the prorenin receptor. This complex is responsible for vacuolar acidification, and reduced function leads to autophagic defects, reduced mammalian target of rapamycin signaling, and indirect abnormalities in protein glycosylation. Low-set ears, micrognathia, and other minor facial findings have been reported. Hepatosplenomegaly associated with liver failure, hypogammaglobulinemia, recurrent infections, and cutis laxa is the most significant somatic abnormality. Growth abnormalities have not been reported.

Abstract This chapter provides pictures and clinical details of NONO-Related XLID, a XLID with variable physical growth, macrocephaly, craniofacial dysmorphism, muscular hypotonia, global developmental delays, noncompaction cardiomyopathy, corpus callosum anomalies, and skeletal anomalies. De novo and maternally inherited truncating variants in the non-POU domain-containing octamer-binding protein gene, NONO, have been demonstrated. Craniofacial features that have been described include macrocephaly, long face with upslanting palpebral fissures, malar hypoplasia, thin and high nasal root, small open mouth, and narrow high-arched palate with dental crowding in some cases, whereas triangular face, widely spaced eyes, downslanting palpebral fissures, malar flattening, and a thin vermilion of the upper lip have been described in other cases.

Abstract This chapter provides pictures and clinical details of Atkin-Flaitz syndrome, an XLID with short stature, macrocephaly, coarse facial features, broad short hands with tapered fingers, macroorchidism, and seizures. The gene has not been identified. Macrocephaly, large forehead, prominent supraorbital ridges, hypertelorism, broad nasal tip with anteverted nostrils, and thick lower lip give the distinctive facial appearance. Large ears, downslanted palpebral fissures and micrognathia may also be present. Seizures occur in a minority. Carrier females are less severely affected, having mild cognitive impairment, large forehead with prominent supraorbital ridges, hypertelorism, broad nasal tip, and thick lower lip. They are short and tend to be obese.

Abstract XLID caused by cerebral creatine deficiency with decreased muscle mass, hypotonia, expressive language impairment, seizures, and aberrant behavior. Mutations in the solute transporter SLC6A8 are the cause and may represent one of the most common causes of XLID (1–3%).

Abstract This chapter provides pictures and clinical details of Young-Hughes syndrome, an XLID with short stature, obesity, hypergonadotropic hypogonadism, chronic dermatitis, strabismus, and seizures. The gene has not been localized. The facies show short palpebral fissures, strabismus, and low-set and cupped ears. Optic nerve hypoplasia, nystagmus, and myopia may be present. Short stature, obesity, underdevelopment of the genitalia, and scant sexual hair dominate the phenotype. The skin is chronically and variably affected with dryness, atopia, ichthyosiform scaling, and excoriation. Generalized seizures appear common. The voice is high-pitched. Low birth weight is followed by short stature and obesity during childhood and beyond. Developmental milestones are globally delayed. Carrier females have normal intelligence and normal stature, and they exhibit none of the somatic features seen in affected males.

Abstract This chapter provides clinical details of Galloway-Mowat syndrome 2, an XLID with microcephaly due to neuronal migration anomalies and cerebellar hypoplasia, nephrotic syndrome, and lethality in early childhood. The gene associated with this disorder, LAGE3, is involved in transcriptions, translation, and genome maintenance. The typical craniofacial findings are microcephaly with narrow forehead, hypertelorism, deep-set eyes, large ears, and micrognathia in some patients. Glomerular lesions become manifest early as nephrotic syndrome. Some patients have scoliosis and arachnodactyly. Intrauterine growth impairment continues postnatally with microcephaly and short stature. Development is globally delayed. Carrier females are clinically normal and may show skewed X-inactivation.

Abstract This chapter provides pictures and clinical details of X-linked agenesis of the corpus callosum. Maldevelopment of the corpus callosum may occur as an isolated and perhaps asymptomatic finding or may coexist with other anomalies. XLID syndromes that may have dysgenesis of the corpus callosum include Aicardi, ARX-Associated XLID, Bertini, Cerebro-Oculo-Genital, Hydrocephaly-MASA spectrum, Juberg-Marsidi-Brooks, Kang, KCND1-Related XLID, Lujan, MIDAS, Multiple Congenital Anomalies-Hypotonia-Seizures 2, NONO-Related XLID, Optiz FG, Oral-Facial-Digital I, Proud, Pyruvate Dehydrogenase Deficiency, Raymond Type XLID, RNF113A-Related XLID, SH3KBP1-Related XLID, TARP, X-Linked Lissencephaly, XLID-Brain Anomalies-Ataxia, XLID-Multiple Anomalies-Early Lethality, XLID-Nystagmus-Seizures, and ZFX-Related XLID. Although a number of families with apparently X-linked partial or complete agenesis of the corpus callosum have been reported, it is not clear that they do not represent one of these syndromes.

Abstract XLID with short stature, small head, hypotonic facies, and brachydactyly. Carpenter-Waziri Syndrome is allelic to Alpha-Thalassemia Intellectual Disability (XLID-Hypotonic Facies), Chud-ley-Lowry, XLID-Arch Fingerprints-Hypotonia, and Holmes-Gang syndromes, caused by alterations in the ATRX gene.

Abstract XLID with short stature, microcephaly, narrow or triangular face, telecanthus, epicanthus, upslanting palpebral fissures, cupped ears, and ectodermal manifestations. A missense mutation in PQBP1 has been demonstrated, making Golabi-Ito-Hall syndrome allelic to Renpenning, Hamel Cerebro-Palato-Cardiac, Sutherland-Haan, and Porteous syndromes.

Abstract XLID with hypocalcemia, seizures, and cataracts secondary to hypoparathyroidism. Structural alterations near the SOX3 gene in Xq27.1 may be responsible.