The first patient is a female who came to our attention aged 2 years. SRS was suspected due to SGA, poor postnatal growth, failure to thrive and hypotonia.

She is the fourth child of unrelated parents, coming from different regions in Morocco. Her family history was negative for inherited diseases. Prenatal infectious screenings were unremarkable, but a prenatal ultrasonography showed intra-uterine growth restriction (IUGR). She was delivered at 35 + 3 weeks of gestation age by caesarean section because of spontaneous onset of labour.

At birth, weight was 1622 g (-2.07 SDS), length 43 cm (-1.37 SD), and head circumference 30 cm (− 1 SD). APGAR score at the first and fifth minute of life were 7 and 8. She developed transient hypoglycaemia, treated with an intravenous glucose infusion.

At the time of examination, she showed dolichocephaly, a prominent forehead, bitemporal constriction, saddle nose with long philtrum, a prominent upper lip, micrognathia and ogival palate (Figs. 1 and 2). Delayed motor development and hypotonia were present. Blood tests were normal except for a mild elevation of aminotransferase, with normal creatinine kinase. Echocardiogram and ophthalmological evaluation were normal. Brain magnetic resonance imaging (MRI) showed mild hypoplasia of vermis and corpus callosum. She weighed 6.4 Kg (-7.5 SD) and was 75.4 cm (-2.75 SD) long.

Clinical photograph of patient 1, frontal view: note bitemporal constriction, saddle nose with long philtrum and a prominent upper lip

Clinical photograph of patient 1, lateral view: note dolichocephaly, a prominent forehead, micrognathia

At 3 years of age, she weighed 7.5 Kg (-7.1 SD) and was 81.3 cm (-3.3 SD) long.

At 4 years and 7 months of age she showed language difficulties and motor delay. Her growth values were height 93.5 cm (-2.5 SD), weight 10.5 kg (-4.8 SD), body mass index (BMI) 12 Kg/m3 (-3 SD), growth velocity 5.4 cm/year (-1.1 SD), with mild bone age retardation (4 years).

Poor growth was associated with low levels of IGF-1, and she began therapy with recombinant Growth Hormone (GH) aged 5, with good clinical response. At the age of 6, she developed early puberty and was ok treated with GnRH analogue. She developed mild hypermetropia and strabismus over time, and her muscular strength and tone markedly improved.

Minor dysmorphic findings, severe growth retardation and marked muscular hypotonia prompted genetic analysis seeking an underlying genetic cause.

Genetic workup ruled out Wolf Hirschhorn syndrome, Fluorescent in situ hybridization [(FISH) 4p16.3] and Prader-Willi syndrome [FISH 15q11.2] and the methylation studies were both normal). Her karyotype was normal (46, XX).

Therefore, a Array -Comparative Genomic Hybridization (CGH-Array) was performed, which showed a de novo 1 Mb deletion of the chromosome 14 in the q32.2-32.31 imprinted region arr [hg19] 14q32.2-32.31 (100449043–101488936)x1 A microsatellite segregation analysis showed maternal only microsatellites in the deleted region, establishing that the deletion was on the paternal chromosome 14, and resulting in a diagnosis of Temple syndrome (TS14).TS14 by microdeletion have been described and reported in literature [8].

The second patient is an Asian male who came to our attention aged 1 year and 3 months with short stature and feeding difficulties since birth. He was born via caesarean section without complications at 38 + 1 weeks of gestation after a spontaneous pregnancy with a birth weight of 2230 g (-2.38 SD), a length of 44 cm (-2.65 SD), and a head circumference of 33,1 cm (-1 SD). Since the first days of life, he showed failure to thrive.

At 5 months, at first genetic evaluation, facial dysmorphisms were noted, including a slightly triangular face characterized by a broad, slightly rounded and protruding forehead, slight epicanthus, a small angioma of the nasal root, short philtrum, pointed chin and low-set ears (Figs. 3 and 4). He also had sternal bone spurs and mild diastasis of the rectus abdominis muscles, a Mongolian patch on the left ankle and in the sacral region, and fifth finger clinodactyly, without any skeletal asymmetry. Screening for metabolic disease was negative (urinary and blood amino acids and urinary organic acids). At the time of evaluation his weight was 4.150 g (-5 SD), his length 60 cm (-2.7 SD), and head circumference 38.5 cm (-3.5 SD).

Clinical photograph of patient 2, frontal view: note triangular face characterized by a broad, slightly rounded and protruding forehead, slight epicanthus, a small angioma of the nasal root, short philtrum, pointed chin

Clinical photograph of patient 2, lateral view: note a prominent forehead and low-set ears

At 1 years and 3 months his growth was still harmonic with a weight of 7600 g (-2.7 SD), a length of 73.5 cm (-2 SD) and head circumference of 43.2 cm (-2.7 SD).

A karyotype and a molecular analysis for SRS (chromosome 7 and chromosome 14 UPD research, a CGH Array and IC1 methylation analysis) were performed with normal results.

Because the clinical phenotype was highly consistent with SRS, further genetic testing to investigate possible SRS-like syndromes was performed, showing a maternal uniparental disomy of the entire Chromosome 20 (UPD20), an imprinting disorder known as Mulchandani-Bhoj-Conlin Syndrome (OMIM# 617352) [9].

The third patient is an Italian male referred aged 19 months. SRS was suspected because of postnatal growth defect and mild craniofacial dysmorphisms. He also manifested language delay, failure to thrive, and atopic eczema. He was the youngest of five siblings. His family history was positive for a growth defect in his brother. Gestation and neonatal periods were regular. He was born at 38 weeks of gestational age with a birth weight of 2550 g (-1.5 SD), a length of 47 cm (-1,5 SD) and a head circumference of 32 cm (-2 SD). At the time of examination, motor development was consistent with his age, but he showed mild expressive language delay (he could only say one word). Parents report feeding difficulties during his postnatal period. At 19 months, he showed severely impaired growth with a weight of 9,6 Kg (-1.5 SD), a height 74 cm (-3 SD), a head circumference of 44 cm (-2 SD). On clinical examination, he was observed to have a wide nasal root, a hint of epicanthus on the left, elongated eyelashes and microretrognathia.

At 4 years and 5 months of age his weight was 12,5 Kg (-2.5 SD), his height was 93 cm (-3 SD), his BMI was 14,5 (-1.5 SD) and his head circumference was 46 cm (-3 SD). He underwent genetic analysis because of the suspicion of a syndromic short stature condition. CGH array showed a microduplication of 1.2 Mb in the 5q35.2q35.3 region (arr[hg19] 5q35.2q35.3(175839681–177047120)x3, encompassing the NSD1 gene. Both his brother affected by growth delay and his mother tested positive for the same microduplication, assessing the same diagnosis of NSD1 duplication-associated syndromic short stature in both brothers and likely in the mother.

NSD1 duplication are associated with duplication-related SRS-like 5q35 condition. The clinic of his brother was consistent with poor growth. At birth his weight was 2650 g (-1 SD), his length was 47 cm (-1.5SD), and his CC was 34,5 cm (-0.3 SD). at the time of the evaluation he was 12 years old. His weight was 29 Kg (-1.5 SD), his height was 132 cm (-2 SD), and his head circumference was 48 cm (-3 SD). About his facial characteristics he has synophrys, reverse epicanthus, and thin vermillions.

The mother of the children has a harmonic short stature. She referred that she needed a scholar support during her infancy. Unfortunately we didn’t have the possibility to reach more informations, but looking at the hereditary model and the high penetrance of this condition we could make the same diagnosis in all the three family members.

After the diagnosis, a more accurate neurodevelopmental evaluation was done at the age of 30 months, showing an IQ of 71 points on a Griffiths scale. An echocardiography ruled out congenital heart diseases.

The fourth patient was referred aged 14 months and he was the only male child born from healthy non-consanguineous parents admitted to the genetic paediatric department of our Institute due to short stature.

His gestation was characterized by IUGR and polyhydramnios and was born via an induced delivery at 38 weeks of gestational age.

His birth weight was 2530 g (-1.5 SD), length 48 cm (-1 SD) and head circumference 34 cm (-0.4 SD). His poor growth was confirmed also during his postnatal life.

His physical examination evidenced triangular face, prominent forehead, depressed (deeply set) eyes, bulbous nose, micrognathia, short philtrum and thin vermillion. He had an apparently inhomogeneous distribution of subcutaneous adipose tissue, concentrated in the upper body, especially arms, becoming more evident with increasing age. His weight was 7100 g (− 3 SD), length 72 cm (− 2.5 SD), head circumference 44,6 cm (-1.5 SD). A cardiac ultrasound revealed a small patent foramen ovale. Electrocardiogram (ECG), abdominal ultrasound and transfontanellar ultrasound were normal.

A CGH array study showed a de novo 300 kb microdeletion at 18q21.32, of uncertain significance.

Analysis of 11p15.5 ICR1/ICR2 and maternal UPD7 studies showed a normal methylation pattern. Due to the high suspicion of SRS or SR-like syndromes, Next generation sequencing analysis (NGS) of IGF2, CDKN1C, PLAG1, PIK3RI, HMGA2 and other genes associated with the clinical characteristics of the patient was performed, revealing a point pathogenetic heterozygous mutation on the PIK3RI gene (NM_181523.3:c.1945 C > T, p.Arg649Trp), pathogenetic for SHORT syndrome.