Updating the neurodevelopmental profile of Alazami syndrome: illustrating the role of developmental assessment in rare genetic disorders

Abstract

Alazami syndrome, caused by biallelic pathogenic variants in LARP7, is a recently-described rare genetic disorder, with 17 patients currently reported in the literature. We present a case of a male infant referred for genetics evaluation at 5 months of age, found at 17 months of age to have Alazami syndrome. He was promptly referred for developmental evaluation, where he was found to be higher functioning than prior reports of individuals with this condition. This demonstrates the neurodevelopmental phenotypic variability seen in rare genetic disorders; it also demonstrates the important role of developmental programs to measure and track outcomes and provide support for infants with genetic disorders that put them at risk of developmental disabilities.

INTRODUCTION

Alazami syndrome (MIM 615071) was first described in 2012 in a consanguineous Saudi Arabian family with a syndromic form of primordial dwarfism caused by homozygosity for a protein-truncating variant in LARP7 (Alazami et al., 2012), a gene that had been recently implicated as a cause of intellectual disability (Najmabadi et al., 2011). The affected individuals in the family described by Alazami et al had substantial growth retardation and severe intellectual disability in addition to shared facial features such as deep-set eyes and malar hypoplasia (Alazami et al., 2012). Since the initial description of this syndrome, an additional 7 individuals have been reported, with varying descriptions of intellectual disability and developmental delay (ID/DD). Most patients are reported to have moderate to severe ID and global developmental delay, particularly delayed speech. In fact, only one patient is reported to have meaningful speech (Hollink et al., 2016), though these details are not consistently provided, and the younger patients reported may have yet to develop additional language skills. These individuals also share a unique facial gestalt with the initial family described and are all reported to have pathogenic protein-truncating variants in LARP7 (Dateki et al., 2018; Hollink et al., 2016; Holohan et al., 2016; Imbert-Bouteille et al., 2018; Ling & Sorrentino, 2016). The age at diagnosis ranges from 2 to 26 years of age and many families are reported to be consanguineous (Dateki et al., 2018; Hollink et al., 2016; Holohan et al., 2016; Imbert-Bouteille et al., 2018; Ling & Sorrentino, 2016).

While many monogenic disorders present with ID/DD (Soden et al., 2014), particularly newly-described conditions (Najmabadi et al., 2011; Wright et al., 2015), details regarding the developmental phenotype are often scarce. Literature reports typically describe the age at which basic milestones were met and an estimate of the degree of ID, though information regarding specific assessments or the results of an evaluation by a developmental specialist are rarely provided. In the era of “reverse phenotyping,” it is likely that the phenotypic spectrum for many of these conditions will broaden as additional individuals, particularly those who are younger, are diagnosed with these rare conditions. The developmental prognosis of rare conditions such as Alazami syndrome is therefore uncertain and will continue to be shaped by additional patient descriptions. We present a new case of Alazami syndrome diagnosed by clinical exome sequencing at 17 months of age, the youngest reported patient to date, with particular attention to his developmental status as an example of the importance of developmental assessment for patients with rare genetic disorders.

CASE PRESENTATION

A 5-month-old male infant was referred to our genetics clinic for an initial evaluation due to failure to thrive, short stature, and concern for aspiration in addition to unique facial features. He was the 2.63 kg, 47 cm long product of a 40 week pregnancy born by spontaneous vaginal delivery to a 32-year-old gravida 1, para 0 to 1 mother and a 32-year-old father. The pregnancy was notable for intrauterine growth restriction and concern for short long bones. He had an unremarkable postnatal course initially though was referred to multiple specialists by 5 months of age due to poor weight gain and linear growth. He was found to have aspiration on a swallow study and was transitioned to thickened formula. An evaluation by otorhinolaryngology, including flexible nasal endoscopy and laryngoscopy, was unremarkable. An electrocardiogram and evaluation by a cardiologist was unremarkable. He was evaluated by endocrinology for poor growth and had normal thyroid function tests, borderline low cortisol that was normal upon repeat and normal prolactin, random growth hormone, and IGF-1. Upon evaluation by a neurologist at 6 months of age due to his history of aspiration and concern for hypertonia, he was found to have moderate hypertonia throughout with normal deep tendon reflexes. A head ultrasound showed mild ventriculomegaly and a brain MRI showed a thin corpus callosum and a disorganized foliar pattern in the cerebellar hemispheres. His family history was unremarkable with no history of consanguinity. His paternal ancestry was German and Northern European and maternal ancestry was Italian, Scottish, English, and Mexican.

On physical examination at his first visit to genetics at 5 months of age, his weight was 6.4 kg (11%ile), length was 61.4 cm (4%ile) and head circumference was 43 cm (49%ile). He was noted to have a prominent forehead, a depressed nasal bridge, thin upper lip, and mild micrognathia. Upon subsequent evaluations, he was also noted to have overlapping of the second and fourth toes over the third toe and rough skin over his feet. By 2 years of age he was 11.0 kg (8%ile) with a height of 81.4 cm (4%ile) and head circumference of 50 cm (80%ile).

A skeletal survey was obtained at 8 months of age and showed a subjectively large calvarium and bone age that was two standard deviations above stated age, but was otherwise not indicative of a skeletal dysplasia. His initial genetic evaluation consisted of a G-banded karyotype (ARUP Laboratories, Salt Lake City, UT), chromosomal microarray (custom whole genome array consisting of comparative genomic hybridization plus single nucleotide polymorphism) and testing for hypochondroplasia/achondroplasia via targeted mutation analysis of FGFR3 that were unremarkable (Claritas Genomics, Cambridge, MA). Plasma amino acids, blood acylcarnitine profile, and total and free carnitine obtained to evaluate for an inborn error of metabolism causing developmental delay were normal.

METHODS

Editorial Policies and Ethical Considerations

Written informed consent was obtained from the parents on behalf of the proband for clinical exome sequencing and for the publication of photographs.

Exome Sequencing

Diagnostic trio exome sequencing was performed for the proband and both parents by a clinical laboratory (GeneDx, Gaithersburg, MD).

RESULTS

Exome Sequencing

At age 17 months, clinical exome sequencing revealed biallelic variants in LARP7: (NM_016648.3) c.834dupA, p.(Arg279ThrfsTer5) (pathogenic) and c.646+5G>C, (IVS6+5G>C) (likely pathogenic). The first variant creates a premature stop codon and the second variant is intronic and predicted to cause abnormal gene splicing by loss of a splice donor site. These variants were orthogonally-confirmed in the proband via Sanger sequencing at GeneDx. The finding of these two variants in trans was consistent with a diagnosis of Alazami syndrome.

Developmental Evaluation

In terms of his developmental milestones, the infant was able to roll from front to back by 5 months of age. He was able to sit independently between 6–7 months of age. He developed a pincer grasp by 8 months of age. He began to take independent steps by 14 months of age. After his genetic diagnosis, he was referred for evaluation at the Developmental Medicine Center at our institution.

At 22 months of age, by direct assessment by a licensed clinical neuropsychologist using the Bayley Scales of Infant and Toddler Development, third edition (Bayley-III), the toddler was found to demonstrate overall cognitive abilities in the borderline range, consistent with a 15-month age equivalent. Language emerged as an area of relative weakness, with an overall performance in the extremely low range. Within this domain, receptive communication was somewhat stronger than expressive communication, with scores in the borderline and extremely low ranges, respectively. His receptive language performance on the Bayley-III corresponded to an age equivalent of 13 months, and his expressive language was consistent with a 7-month age equivalent. In terms of motor skills, overall performance was in the borderline range, with gross- and fine-motor skills consistent with a 16-month age equivalent.

To assess his adaptive skill development and as a measure of his functioning outside of the testing environment, parents were administered the Vineland Adaptive Behavior Scales, 3rd edition (Vineland-3) in interview format by a developmental behavioral pediatrician. Results were quite consistent with those obtained through the Bayley-III, and parent report yielded an overall adaptive composite score in the borderline range. In specific skill areas, age equivalents also were largely commensurate, with language estimates 2 months higher, fine-motor skills 5 months higher, and gross motor skills 2 months lower than those obtained on the Bayley-III. Parent report on the Vineland-3 further indicated overall socialization in the borderline range, and daily living skills in the low average range.

Perhaps most notable from a strengths perspective was this child’s social nature. A healthy attachment to his parents could be appreciated; he appropriately sought comfort from them and frequently looked to them to share his enjoyment. He presented as friendly and engaging, and consistently responded to praise and attention. While not yet using words or word approximations, he utilized gestures, some signs, and eye contact to communicate with others.

Based on the information collected throughout this evaluation, the continuation of Early Intervention services was recommended. This included ongoing occupational therapy and intensified speech and language intervention. Participation in a developmental play group also was recommended to aid in the development of language and play skills in a social setting. Finally, the importance of close monitoring of skill development and planning for his transition into preschool on his third birthday was highlighted.

DISCUSSION

We describe a male infant who, at 17 months of age, is the youngest patient diagnosed with Alazami syndrome to date. He is also the first reported patient with an intronic variant predicted to cause abnormal splicing, as the variants previously reported in the literature are frameshift variants resulting in a prematurely truncated protein (Alazami et al., 2012; Dateki et al., 2018; Hollink et al., 2016; Holohan et al., 2016; Imbert-Bouteille et al., 2018; Ling & Sorrentino, 2016). His physical development appears consistent with previous reports of Alazami syndrome, with short stature and characteristic facial features noted in addition to other features particular to Alazami syndrome such as overlapping toes and rough skin over his feet.

Regarding his psychosocial development, our patient was found on developmental assessment to be higher functioning than prior reports (Table). Indeed, the only patient reported in the literature to have spoken words is reported to have two-word sentences at 5 years of age, and there are reports of individuals with Alazami syndrome diagnosed in their second decade of life who still have no speech. Our patient ultimately said his first words at 2 years of age. He also began walking earlier than any other patient reported, and at 14 months, this motor milestone was not delayed. This may be related to his early age of diagnosis and prompt referral for developmental support services and also reflects the engagement of his parents in promoting his developmental progress. It is also possible that his particular and unique genotype – compound heterozygosity for a frameshift variant in addition to an intronic variant – may confer a milder developmental impact. However, as with other very rare disorders, the published literature is sparse regarding developmental outcomes and direct comparisons are difficult. This is seen not only in very rare disorders such as Alazami syndrome, but also in more common and widely-recognized syndromes such as Down syndrome (de Graaf, Levine, Goldstein, & Skotko, 2018). In fact, the most recent case series regarding Alazami syndrome reports severe intellectual disability in 17/17 patients reported (Imbert-Bouteille et al., 2018). However, only one prior report (Najmabadi et al., 2011) mentions a specific test used to evaluate for intelligence quotient (IQ): the Wechsler Intelligence Scales for Children (WISC). Additionally, a recent presentation of a 2-year-old child with Alazami syndrome reports an IQ of 67, which is not in the severe range for ID (Dateki et al., 2018). Furthermore, while one previously-reported patient that was diagnosed in early childhood did have a neuropsychological evaluation, she did not have cognitive testing performed due to her young age, per the report (Ling & Sorrentino, 2016). Therefore, it remains to be demonstrated whether patients diagnosed at a younger age with this condition may have improved developmental outcomes compared to those in the literature.

Table.

Developmental profiles of patients with Alazami Syndrome.

Author (Year)	Najmabadi (2011)	Alazami (2012)									Ling (2016)	Hollink (2016)		Holohan (2016)	Dateki (2018)	Imbert-Bouteille (2018)		Present case
Age at Diagnosis	2 family members, unknown age	12 Y	5 Y	22 Y	20 Y	15 Y	17 Y	10 Y	8 Y	5 Y	2 Y	6 Y	2.5 Y	8 Y	2 Y	22 Y	26 Y	17 M
Genotype NM_016648.3	c.827dup , p.(Lys277GlufsTer7) [homozygous]	c.1024_1030dupAAGGATA, p.(Thr344LysfsTer9) [homozygous]									c.213_214dup p.(Ser72TyrfsTer10) and c.651_655del p.(Lys219GlufsTer30)	c.1091_1094 del, p.(Lys364ArgfsTer12) [homozygous]	c.1024_1030 dup, p.(Thr344LysfsTer9) [homozygous]	c.756_757del, p.(Arg253IlefsTer6) [homozygous]	c.349del, p.(Glu117LysfsTer38) and c.620−646+25del, p.(Phe185LysfsTer13)	c.503_504dup p.(Ala169LeufsTer37) [homozygous]		c.834dupA, p.(Arg279ThrfsTer5) and c.646+5G>C, (IVS6+5G>C)
Developmental outcome	severe ID	DA 4 Y	DA 1 Y	DA 2 Y	DA 2 Y	DA 2 Y	DA 4 Y	DA 4 Y	DA 5 Y	DA 3 Y	ND	DA 22 months at 5 years of age, IQ 37	DA 1 Y	moderate delays	mild ID, IQ 67	severe ID	severe ID	15M age equivalent at 22M of age†
Language skills	ND	ND	ND	ND	ND	ND	ND	ND	ND	ND	No word at 2 Y	2-word sentences at 5 Y	No words at 2.5 Y	ND	No words at 2 Y	No words at 22 Y	No words at 26 Y	First words at 2 Y Language skills <1st%ile†
Motor skills	ND	ND	ND	ND	ND	ND	ND	ND	ND	ND	Walked at 2 Y	Walked at 18 M	Sat 9 M stand 2 Y, walk 27 M	ND	Held head up at 9 M, rolled at 10 M, walked at 2 Y	ND	ND	Rolled at 5 M, sat at 6 M, walked at 14 M Motor skills at 5th%ile†
Behavioral concerns	ND	ND	ND	ND	ND	ND	ND	ND	ND	ND	anxiety, hyper-sensitivity	anxiety related to loud noises	ND	ND	ND	anxiety	anxiety	None noted.

Y, years; M, months; DA, developmental age; ID, intellectual disability; IQ, intelligence quotient; ND, no data.

^†Per the Bayley Scales of Infant and Toddler Development, Third edition (Bayley-III).

As developmental prognosis and anticipated functional status is highly important to parents (de Graaf et al., 2018), particularly those first learning of a new genetic diagnosis, further efforts to better describe the developmental outcomes for rare genetic syndromes are needed.

Figure.

Photographs of the patient at two years of age demonstrate a prominent forehead, malar hypoplasia, a flat nasal bridge, thin upper lip, and mild micrognathia (A,B) and overlapping of the second and fourth toes over the third toe (C) consistent with the diagnosis of Alazami syndrome.