Abnormalities

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  Growth. Macrocephaly (HC) above the 50th centile in early childhood; accelerated linear growth in childhood; however, growth velocity slows at adolescence. Obesity with a subset having a Prader-Willi phenotype (hyperphagia and hypogonadism).

  
  
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  Performance. Generally moderate to profound intellectual disability (ID) in males with intelligence quotients (IQs) of 30 to 55, but sometimes extending into the mild ID to borderline normal range. Hand flapping or biting (60%) and poor eye contact (90%). Perseverative speech in mildly affected males, short bursts of repetitive speech in more severely affected males, and complete lack of speech in severely and profoundly affected males.

  
  
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  Strong gaze avoidance, social avoidance, tactile defensiveness, hyperactivity, hyperarousal, anxiety, poor impulse control, aggressive outbursts. Sensitivity to stimuli, leading to serious behavior problems in overstimulating situations. Autism spectrum disorder (60%). Mean IQ for females 82. IQ below 70 in approximately 30% to 50% of females with the full mutation, and IQ below 85 in 50% to 70%. Significant sleep problems.

  
  
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  Craniofacial. Prominent forehead, elongated face, prognathism usually not noted until after puberty, thickening of nasal bridge extending down to the nasal tip, large ears with soft cartilage, pale blue irises, epicanthal folds, high arched palate, dental crowding.

  
  
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  Connective tissue. Pectus excavatum, excessive laxity of joints, particularly the finger joints; soft skin to mild cutis laxa; flat feet; scoliosis; mitral valve prolapse; aortic prolapse; tricuspid and pulmonary insufficiency; aortic dilation. Dilated ureters and vesicoureteral reflux.

Occasional Abnormalities

Nystagmus, strabismus, seizures, hyperopia, myopia or astigmatism, hypotonia, torticollis, cleft palate. Abnormal ossifications patterns in multiple bones.

Natural History

Life span is normal. Hypotonia, feeding problems, and gastroesophageal reflux are common in infancy, as is otitis media. Growth rate is slightly increased in the early years, with delayed motor milestones such that early features may suggest Sotos syndrome. Testicular size increase becomes more obvious after puberty. IQ typically declines with age.

Factors, such as nurturing home and school environments, have been associated with improved performance. Cognitive training, behavioral therapy, and medications have been identified as promising therapeutic interventions, some of which have been tested in clinical trials. Metformin appears to improve cognition and behavior. Oral Cannabidiol solutions caused noticeable reductions in social avoidance and anxiety, as well as improvements in sleep, feeding, motor coordination, language skills, anxiety, and sensory processing. Treatments of specific molecular targets, such as metabotropic glutamate receptor 5 and GABAB receptor, have been explored in clinical trials. Reactivation of transcription of the FMR1 gene is being investigated as a potential approach for FXS treatment.

Etiology

FMR1 -related disorders include FXS, fragile X-associated tremor/ataxia syndrome (FXTAS), and FMR1 -related primary ovarian insufficiency (POI).

Expansions of a trinucleotide repeat (CGG) in the promoter (5’ untranslated region) of the FMR1 gene located at Xq27.3 cause this spectrum of X-linked conditions. Other loss-of-function mutations or deletions in the gene can occasionally cause FXS.

Normal individuals have from 6 to 54 repeats. Both male and female premutation carriers have 54 to 200 repeats, whereas affected individuals have more than 200. Three factors contribute to greater repeat instability in FMR1 premutation alleles leading to expansion: (1) the transmitting parent, (2) increased repeat size, and (3) the lower number or absence of AGG interruptions within the CGG repeats. For allele sizes above 100 repeats, premutation will always expand in female meiosis, so 50% of their sons will have FXS. Daughters of males with premutation will all be premutation carriers, and 50% of their sons may have FXS. Based on random X-inactivation, the risk that the daughter of a premutation carrier female will be clinically affected is smaller (∼15% to 30%, depending on the size of the premutation allele). Intermediate alleles in the gray zone (45 to 54 repeats) may also expand in female meiosis to premutation alleles and lead to FXTAS or POI. Preconceptional carrier testing is offered increasingly. Prenatal diagnosis in amniotic fluid is offered for women with premutations.

Female premutation carriers have a 20% risk for POI and mood and anxiety difficulties. Premutation carriers may develop deficits in executive function, progressive cerebellar ataxia and tremor, dementia, parkinsonism, and white matter lesions on MRI in the middle cerebellar peduncles and/or brain stem, a constellation of findings referred to as fragile X–associated tremor/ataxia syndrome (FXTAS). Roughly 38% of male and 17% of female premutation carriers have developed some signs of FXTAS after age 60. FXTAS may affect 3% to 5% of adults older than 50 years with essential tremors and is the most frequent cause of ataxia after age 50. Neuropsychiatric disorders are the most common problems associated with the premutation, and they affect approximately 50% of individuals. Anxiety, attention deficit/hyperactivity disorder (ADHD), social deficits, depression, obsessive compulsive disorders, or autism spectrum disorders (ASD). Because of their typically milder phenotype, females may have more potential to attain a higher level of independence and quality of life with a constellation of cognitive, behavioral, and, particularly, socioemotional challenges.

Comment

Expansion of the triplet repeat in FMR1 leads to hypermethylation of the CGG repeats and CpG dinucleotides in the promoter region and to histone modifications leading to transcriptional silencing. Absence of the gene product, FMRP, a selective mRNA binding protein, alters translational regulation of its multiple mRNA partners, which affects synaptic plasticity and function in dendrites in the brain in FXS. Neuroimaging has identified abnormalities in total white matter volume and regional gray matter volumes in FXS. There are correlations between neuroanatomy, FMRP levels, and IQ in FXS. Both premutation and active full mutation alleles often express elevated levels of mRNA that are thought to be toxic. These appear to be the key to development of symptoms in premutation carriers. Mosaicism can occur in 20% of cases, both for CGG repeat size and for degree of methylation. Rarely, individuals with methylation mosaicism or completely unmethylated full mutations and normal intellect have been reported.

Occasional Abnormalities

Psychosis, strabismus, myopia, nystagmus, optic disc pallor and retinal atrophy, cataracts, iris hypoplasia, glaucoma, pectus excavatum, diaphragmatic hernia, abnormal glucose tolerance test (14%). Imaging: normal bone age, white matter demyelination, arachnoid cyst.

Natural History

Maternal preeclampsia occurs in 15% of pregnancies of children with Sotos syndrome. Neonatal problems are frequent, including jaundice, hypotonia, and difficulty feeding. An increased incidence of otitis media has been noted, with conductive hearing loss and associated complications. Early developmental milestones are delayed. However, early assessments, which rely heavily on specific motor and verbal skills that are particularly delayed in Sotos syndrome, may well be poor predictors of ultimate intellectual performance. Even in those patients with normal intelligence, delay of expressive language and motor development is characteristically present in infancy. Behavior problems are common with overlaps with autistic spectrum disorder (ASD) and ADHD. Excessive size, with poor coordination, may lead to problems of social adjustment, often with undue aggressiveness and temper tantrums. Immaturity persisting into adulthood adds to the difficulties with socialization. A variety of psychiatric problems have been noted in some adults. A propensity to fracture with minimal trauma has been documented. A slightly increased risk for malignancy appears to exist (2.2%). Reported tumors include acute leukemia, sacrococcygeal teratoma, neuroblastoma, Wilms tumor, lymphoma, epidermoid carcinoma of the vagina, mixed parotid tumor, hepatocarcinoma, hepatoblastoma, blastoma and small cell carcinoma of the lung, yolk sac tumor of the testis, and diffuse gastric carcinoma. Benign tumors include osteochondroma, ganglioglioma, fibromas of the heart and ovary, and presacral ganglioneuroma. Because the sites and types of tumors vary greatly, no routine screening—with the exception of periodic clinical evaluation—seems appropriate.

Etiology

This disorder has an autosomal dominant inheritance pattern. Most cases are sporadic. Mutations in or deletion of NSD1 (nuclear receptor SET-domain-containing protein), a histone methyltransferase involved in epigenetic regulation, located at 5q35 is responsible for most cases. Gene deletions tend to be associated with greater intellectual disability and more structural anomalies. In the Japanese population, a recurrent 1.9 Mb microdeletion, including NSD1, is the most common molecular finding, whereas point mutations are more common in the non-Japanese. A highly specific and sensitive NSD1 epigenetic signature affects genes that function in cellular morphogenesis and neuronal differentiation.

Comment

Mutation or deletion of NSD1 is only found in 60% to 90% of patients identified as Sotos or Sotos-like without mutation, indicating several overlapping phenotypes lead to a diagnosis of Sotos syndrome.

Mutations in NFIX cause Malan syndrome, previously known as Sotos 2, with a distinct phenotype. Whereas facial dysmorphism in patient who are NSD1 -positive is usually very characteristic, it is less so with SETD2 or DNMT3A mutations. Further studies are needed to assess the role of SETD2 and DNMT3A in nonsyndromal intellectual deficiency without overgrowth. Both NSD1 and SETD2 genes encode epigenetic “writer” proteins that catalyze methylation of histone 3 lysine 36 (H3K36me). The DNMT3A gene encodes an epigenetic “reader” protein of the H3K36me chromatin mark.

Occasional Abnormalities

Cardiac defects, aortic dilation, pulmonary dilation; cortical dysplasias and periventricular nodular heterotopias; facial asymmetry; highly arched palate and dental crowding, gum hypertrophy; sparse hair; loose and soft skin on the soles of their feet.

Natural history

Individuals with an NFIX deletion or a mutation causing Malan syndrome have less overgrowth than patients with Sotos syndrome, some marfanoid features and somewhat different but overlapping facial features. They have more severe intellectual disability and more often an autism spectrum disorder diagnosis than in those with Sotos syndrome. Cases of microdeletion demonstrated a high prevalence of seizures. The increased prevalence of seizures/epilepsy may be explained by the presence of a contiguous gene disorder.

Etiology

Haploinsufficiency of NFIX has been proposed as the leading causative mechanism in Malan syndrome; both loss-of-function mutations and deletions have been identified. Point mutations of NFIX cluster mostly in exon 2, coding for the DNA-binding domain. Among the reported cases, variants arose de novo , except in one family in which the mother was mosaic. The first familial case has been identified in a family by the authors of this book. There is no genotype‐phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Deletions involving CACNA1A, which is located 109 kb from NFIX, seem to be the main cause of the seizures, and a movement disorder of episodic ataxia, also caused by mutation and deletion in CACNA1A alone. Individuals with Malan syndrome exhibit some marfanoid symptoms and sometimes aortic dilation suggesting dysregulation of the TGF‐β pathway. A possible pathophysiologic link could be the interaction of NFIX proteins with Sloan‐Kettering oncogene SKI, the protein mutated in Shprintzen‐Goldberg syndrome.

Comment

Variants causing Malan and Marshall‐Smith syndrome can be discerned by differences in the site of stop codon formation. Marshall-Smith mutations are scattered through exons 6-10 of the NFIX gene and escape nonsense-mediated mRNA decay, whereas most point mutations causing the Malan overgrowth syndrome are clustered in exon 2. Deletions are a frequent cause of the condition, which indicates haploinsufficiency is the main mechanism in Malan syndrome.