Case#: proband, M, Age of Report: 8 y.o., Ethnicity: British.

CasePresentingHPOs: HP:0008846 (Severe intrauterine growth retardation), HP:0004322 (Short stature), HP:0004325 (Decreased body weight), HP:0040195 (Decreased head circumference), HP:0001510 (Growth delay), HP:0011968 (Feeding difficulties/behavioral feeding difficulties), HP:0001263 (Global developmental delay/psychomotor development delay), HP:0000252 (Microcephaly), HP:0000684 (Delayed eruption of teeth/Dentition), HP:0100543 (Cognitive impairment/delayed intellectual development), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000582 (Upslanted palpebral fissure/upward-slanting palpebral fissures), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0100678 (Premature skin wrinkling/Thin, wrinkled skin), HP:0001187 (Hyperextensibility of the finger joints), HP:0010485 (Hyperextensibility at elbow), HP:0009125 (Lipodystrophy)

CaseHPOFreeText:The proband, 8 years of age, is the first child of non-consanguineous Caucasian parents. There are no manifestations of SHORT syndrome in the family. There is no family history of microcephaly or intellectual disability. Following an otherwise uneventful pregnancy, delivery was induced at 38 weeks of gestation on discovery of severe intrauterine growth restriction. His birth weight was 1.97 kg (<0.4th centile, −3.7 SD).

Despite adequate nutritional intake, the patient's growth was significantly delayed. At 12 months of age, his weight was 6.88 kg (<0.4th centile, −3.2 SD), length was 69.5 cm (1st centile, −2.98 SD) and head circumference was 39.5 cm (<0.4th centile, −5.26 SD). Enteral tube feeding was initiated at 9 months of age, which the patient continues to remain dependent on today. Despite extensive investigation of the proband's feeding disorder, no organic cause was identified, and he was diagnosed with behavioral feeding difficulties. Follow-up consultations revealed a persistent development delay and sustained striking microcephaly. Dentition did not start until the age of 2.5 years. At 6 years of age, his weight was 16.2 kg (1st centile, −2.39SD), length was 105.4 cm (1st centile, −2.47 SD) and head circumference was 43.8 cm (<0.4th centile, −6.16 SD). Skeletal survey and extensive endocrine investigation did not find any abnormalities. The patient has not been formally diagnosed with diabetes and is awaiting an oral glucose tolerance test.

Intellectual and psychomotor development is moderate to severely delayed. The patient first walked at 20 months, first smiled at 3 months and spoke his first words aged 3 years. At his current age of 8 years, he attends a special needs school and requires substantial multidisciplinary support. Magnetic resonance imaging of the brain and electroencephalogram performed at 12 months of age was normal. Neurometabolic investigation was also normal. Recurrent ophthalmology investigations revealed a myopic left eye and hypermetropic right eye at 4 years of age. No anterior chamber defects were noted and his ocular pressure was reported as normal. His hearing was formally assessed and reported as normal.

Facial dysmorphic features are subtle but present (see Figure 2): triangular face, prominent forehead, broad eyebrows, slight upward-slanting palpebral fissures, and hypoplastic alae nasi leading to an impression of low columnella nasi. The patient has thin, wrinkled skin with visible veins, most prominently seen on his chest wall. He has hyperextensibility in his finger and elbow joints. Of note, local lipodystrophy of his proximal finger phalanges is also observed.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Skeletal survey and extensive endocrine investigation did not find any abnormalities. The patient has not been formally diagnosed with diabetes and is awaiting an oral glucose tolerance test.

No anterior chamber defects were noted and his ocular pressure was reported as normal.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Chromosome breakage studies, Angelman methylation studies and a 60 gene developmental delay and epilepsy panel were normal. Comparative genomic hybridization microarray identified a likely benign maternally inherited Xp11.4 duplication (GRch X:38646145-38687854). Trio-exome sequencing revealed a de novo heterozygous missense variant, c.1456G>A (p.Ala486Thr) in PIK3R1 (NM_181523.3).

Variant: NM_181523.3:c.1456G>A (p.Ala486Thr).

ClinVar: N/A.

CAID: CA359881414.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo:N/A.

CasePMIDs: N/A.