Alazami syndrome in an Afghani girl: A case report and review of literature

Purpose: Alazami syndrome is a rare autosomal recessive disorder with core phenotypic manifestations of short stature, mild facial dysmorphism, and global developmental delay evolving to severe intellectual disability. Homozygous loss-of-function mutations in LARP7 gene, which encodes a chaperone protein of the noncoding RNA 7SK, have been detected in patients with Alazami syndrome. Since its fi rst description in 2012, only six families with Alazami syndrome have been reported to date. This case is reported to expand the phenotypic description to include small kidneys. Methods: The patient was referred for Clinical Genetics evaluation at Rady Children’s Hospital San Diego due to intellectual disability and growth delay. Whole exome sequencing was performed (GeneDx) after informed consent. Result: Whole exome sequencing identifi ed a homozygous pathogenic variant in exon 12 of LARP 7(c.1620_1623delACAG; p.Ala542Aspfs*15), conferring a diagnosis of Alazami syndrome. The clinical features of a 16-year-old Afghani girl with Alazami syndrome are reported and compared to features of previously reported Alazami syndrome cases. In addition to sharing many features of previously reported cases, the subject of this report also had small kidneys and pre-hypertension. Conclusion: This case report broadens the phenotype of Alazami syndrome to include small kidneys and behavioral problems related to anxiety. Case Report Alazami syndrome in an Afghani girl: A case report and review of literature Mazen S Alzahrani1* and Lynne M Bird2 1MBBS, University of California-Sand Diego, Health Science International(HSI)Bridge to Residency Program, Sand Diego, CA-USA 2MD, Clinical Genetics/Dysmorphology Professor of Clinical Pediatrics, University of California, Sand Diego Rady Children’s Hospital Sand Diego, CA-USA Received: 21 May, 2019 Accepted: 04 July, 2019 Published: 05 July, 2019 *Corresponding author: Mazen S Alzahrani, MBBS, University of California-Sand Diego, Health Science International-Bridge to residency program, Sand Diego, CA USA, E-mail:


Introduction
Alazami syndrome (OMIM: 615071) is a genetic disorder caused by homozygous or compound heterozygous mutations in LARP7, which encodes a chaperone of the 7SK noncoding (nc) RNA [1]. Alazami et al., [2], fi rst described this syndrome in a large consanguineous Saudi Arabian family, where ten affected children showed primordial dwarfi sm (PD) having growth parameters at least 3.5 SD below the mean, severe intellectual disability, and facial dysmorphism consisting of malar hypoplasia, short philtrum, triangular face, deep-seated eyes, broad nose, narrow palpebral fi ssures, and microstomia [1][2][3]. Additionally, some nonspecifi c skeletal abnormalities such as scoliosis and mild epiphyseal changes in proximal phalanges without clear dysplasia were observed [2]. Genomewide linkage analysis of affected individuals, their parents, and some of the unaffected siblings detected an extended 26.5-Mb homozygous region between SNPs surrounding chromosome 4q24-4q28.2 among all patients but not in unaffected relatives. Molecular functional studies and sequencing of a list of candidate genes in this region showeda homozygous 7 bp duplication in exon 8 of LARP 7 gene (c.1024_1030dupAAGGATA, p.T344Kfs*9), causing a frameshift mutation that resulted in premature truncation of the peptide [2]. A complete absence of LARP7 protein was also observed in the patients suggesting that mutation produced a null phenotype [2].
Najmabadi et al., [4], conducted a large study including 136 consanguineousIranianfamilies with autosomal-recessive intellectual disability and microcephaly and determined the etiology to be a frameshift mutation (Lys276fs) in LARP 7.
Furthermore, Ling et al., [3] with other previously reported Alazami syndrome patients to portray further phenotypic manifestations related to this syndrome.

Case Presentation
The patient wasa 16-year-old girl of Afghan origin with primary complaints of intellectual disability, growth and motor development delay, and dysmorphic facial features, who was referred for outpatient clinical genetics consultation. She was the product of a consanguineous union, and there was a family history of intellectual disability in a paternal aunt and paternal grandmother. Mother reported poor fetal movement, a 7 kg weight loss and depression during the pregnancy. She was delivered at term by cesarean section weighing1.8 kg. Although her growth in the neonatal period was normal, her psychomotor development was delayed and she was able to talk and walk at 3 years age. She is unable to speak full sentences and usually gives one-word answers, fails to follow commands, requires assistance to get dressed, and shows situational anxiety. Physical examination revealed a height of 144.5 cm (z=-2.82) and head circumference of 51.8 (z=-2.5) with narrow, prominent forehead and low posterior hairline. Her nose was broad with a bulbous tip. She had a short philtrum, widely spaced teeth, deeply set eyes, malar fl attening and mildly short palpebral fi ssures (2.5cm) (Figure1). Finger pads were prominent, and the great toes were shorter than the second toes. Streaky hyperpigmentation was observed on her right lateral chest and back of the legs. There was a grey macule on the dorsum of her left hand. She could walk steadily with a wide-based gait but was unable to run. She has hyperopia and strabismus, but is noncompliant with wearing spectacles.
Renal ultrasound with Doppler detected a small left kidney (4 th centile); DMSA scan showed equal fl ow of blood in both the kidneys and normal renal function. Due to strong family history of hypertension, amlodipine was started for prehypertension. Echocardiogram was normal. Audiological evaluation revealed mild conductive hearing loss in both ears. An oligonucleotide SNP microarray showed regions of homozygosity totaling at least 103 Mb, consistent with parental fi rst-cousin relationship, and a 109 kb microdeletion of chromosome 16q21, interpreted as a variant of uncertain signifi cance.
Whole exome sequencing analysis revealed a homozygous 4 bp deletion in exon 12 of LARP7, resulting in a frameshift and creating a premature stop codon (c.1620_1623delACAG; p.A542Nfs*15). Her parents were heterozygous for the c.1620_1623delACAG variant in the LARP7 (Table 1).

Discussion
We presentan additional case of Alazami syndrome characterized by severe intellectual disability, mild facial dysmorphism, mild short stature, and microcephaly due to a novel homozygous frameshift loss-of-function variant in LARP7. LARP7 belongs to the La Autoantigen related protein family and is responsible for regulation of 7SK-mediated transcription by binding to the 3'-terminal domain of 7SK RNA and becoming an intrinsic part of it [7]. LARP7inhibits RNA Polymerase II-transcribed genes by means of the 7SK small ribonucleoprotein (snRNP) system [8]. Some cases have had normal prenatal growth but considerable postnatal growth restriction [3,5]. Our patient's fi nal adult height is not as signifi cantly impaired as the initial case descriptions [2,3,6] and not in the range typical for primordial dwarfi sm, and more in accordance with the growth reported byHollink et al., [1] and Dateki et al. [5].   Motor delay 9 out of 9 + + + + + NR + 88% Intellectual disability 9 out of 9 + + + + + + + 100% Triangular face 9 out of 9 Prominent forehead 9 out of 9 Deeply-set eyes 9 out of 9 + + + NR + 1/2 + 82%

NR=Not reported
Behavioral abnormalities have been reported in Alazami syndrome.Hyperactive behavior was reported by Hollink et al., [1], in one patient and in both patients reported by Imbert-Bouteille M et al., [6]. Furthermore, anxiety, frequent tantrums, and hypersensitivity to stimuli were observed in the patient reported by Ling et al., [3]. Our patient exhibits situational anxiety. These fi ndings suggest that behavioral abnormalitiesare an important feature ofAlazami syndrome.  Our patient has pre-hypertension with a family history of early-onset of hypertension.Additionally, our patient possesses small-sized kidneys (between 4-14% tile). To date, only one other patient has exhibited this feature: Holahan et al., [11], reported small sized kidneys (between 5-10%). Whether the small kidney size is a congenital defect or acquiredand whether this phenotype belongs to the spectrum of billaelicLARP7 mutations remain to be determined.
With more widespread use of WES, we anticipate that the diagnosis of Alazami syndrome will be made in additional patients of all racial/ethnic backgrounds, and we expect the clinical spectrum to continue to broaden.