**3.1. Developmental obesity syndromes involving ciliary dysfunction**

**Syndrome Clinical features in addition to obesity** 

224 Adiposity - Omics and Molecular Understanding

**Cohen**  Retinal dystrophy, prominent central

**Alström**  Retinal dystrophy, neurosensory

**X fragile**  Mental retardation, hyperkinetic

**Ulnar–mammary**  Upper limb malformation (from

glands

obesity

skills

**Table 2.** Main forms of syndromic obesity.

organomegaly.

**Borjeson‐Forssman‐ Lehmann** 

**Albright hereditary osteodystrophy** 

**Simpson‐Golabi‐ Behmel** 

**MEHMO syndrome** 

**1p36 deletion syndrome** 

**16p11.2 deletion syndrome** 

*ACP1***,** *TMEM18***,** *MYT1L* **deletion**

prominent jaw

large ears, epilepsy

facial dysmorphy, hypogonadotrophic hypogonadism, short stature

incisors, dysmorphic extremities, microcephaly, cyclic neutropenia

behavior, macroorchidism, large ears,

Mental retardation, hypotonia, hypogonadism, facial dysmorphy with

Short stature, skeletal defects, facial dysmorphy, endocrine anomalies

hypoplasia of the terminal phalanx of the fifth digit to aplasia of hand and upper limbs on the ulnar side), abnormal development of mammary glands and nipples, teeth, genitalia, and of apocrine

Multiple congenital abnormalities, pre‐/ post‐natal overgrowth, distinctive craniofacial features, macrocephaly, and

Mental retardation, epileptic seizures, hypogenitalism, microcephaly and

Delayed growth, malformations, moderate to severe intellectual disability, seizures, hearing and vision impairment, and certain particular facial features.

Developmental delay, intellectual disability, autism spectrum disorders, impaired communication, socialization

Hyperphagia, intellectual deficiency, severe behavioral difficulties

deafness, diabetes, dilated cardiomyopathy

**Prevalence Genetic** 

Diagnosed in fewer than 1000 patients worldwide

Diagnosed in about 950 patients worldwide

Approximately 50 reported patients

Approximately <1/1,000,000 births

1/5000 to 1/10,000 live births

Approximately 3/10,000 births

Approximately 13 reported patients defect or reciprocal translocation)

(chr 8q22‐q23)

(chr 2p13‐p14)

1/2500 births X‐linked *FMR1* gene (Xq27.3)

1/1,000,000 births Autosomal dominant *GNAS1* gene (20q13.2)

(12q24.21)

Autosomal recessive *COH1* gene

Autosomal recessive *ALMS1* gene

X‐linked *PHF6* gene (Xq26‐q27)

Autosomal dominant *TBX3* gene

X‐linked *GPC4* gene (Xq26)

X‐linked locus MEHMO (Xp22.13‐p21.1)

Autosomal dominant microdeletion of 1p36

Autosomal dominant microdeletion of 16p11.2

genes (2p25)

Paternal deletion encompassing the *ACP1*, *TMEM18*, *MYT1L*

Some genes linked to obesity have been associated with the function or formation of primary cilia, subcellular organelles, which serve a sensory function for most cell types. The ciliopathies form a class of genetic disease whose etiology lies with primary ciliary dysfunction. Some peculiar features can be found, such as retinal degeneration. This feature is of particular interest for its clinical relevance, rarity, and diagnostic power. Between these groups of diseases, we can include the Bardet‐Biedl syndrome (BBS) and Alström syndrome (ALMS).

BBS has become a model ciliopathy because it became the first disease whose etiology lay in primary ciliary disorder [73]. It is a rare autosomal recessive genetic disorder with severe multiorgan impairment [74]. Its frequency in Europe and North America falls below 1:100,000 [75]. The disease symptoms may significantly vary between the patients; therefore, the diagnosis relies on the number of primary and secondary features of BBS [74]. Multiple articles summarize the data on frequencies of various symptoms in BBS patients [75, 76]. However, it is very important to realize that almost all clinical studies analyzed patients of various ages. Many individuals with BBS look virtually healthy at birth unless they were born with a polydactyly. Other symptoms of BBS tend to gradually emerge during or after the first decade of life; thus, patients diagnosed at early childhood tend to have fewer clinical features of the disease [74]. There are six primary features of BBS, that is, rod‐cone dystrophy, polydactyly, obesity, genital abnormalities, renal defects, and learning difficulties. Secondary features include developmental delay, speech deficit, brachydactyly or syndactyly, dental defects, ataxia or poor coordination, olfactory deficit, diabetes mellitus, and congenital heart disease [75]. Some authors also mention hypertension, liver abnormalities, bronchial asthma, otitis, rhinitis, craniofacial dysmorphism, etc. [75–78].

However, the phenotype can be different: generally, obesity occurs early in life of patients affected by BBS, but the literature shows that 52% of post‐pubertal BBS patients are obese [79]. It is recommended to assign BBS diagnosis to patients bearing at least 4 out of 6 primary features of the disease. If only three primary features are detected, two secondary features are required to confirm the presence of BBS.

These criteria describe BBS mainly as a clinical entity; they do not fully account to the existence of patients with attenuated forms of the disease as well as to possible gene‐specific manifes‐ tations of BBS [80, 81].

At least 20 BBS genes have already been identified, and all of them are involved in primary cilia functioning. Genetic diagnosis of BBS is complicated due to lack of gene‐specific disease symptoms; however, it is gradually becoming more accessible with the invention of multigene sequencing technologies [74].

The first five BBS loci were identified via linkage analysis of large BBS pedigrees [82–86] with corresponding genes cloned some years later [87–92]. The first gene assigned to BBS was *MKKS* (*MKS*; OMIM \*604896) already known to induce McKusick‐Kaufman syndrome; given that it did not belong to previously identified BBS loci, it was named *BBS6*. At present, there are already 21 known BBS genes (*BBS1*–*BBS20* and *NPHP1*), and their number is likely to increase due to the invention of exome sequencing and analysis of previously unstudied populations

[74]. Strikingly, all BBS genes participate in cilia functioning, being a part of BBSome (*BBS1* [11q13.2; OMIM \*209901], *BBS2* [16q13; OMIM \*606151], *BBS4* [15q24.1; OMIM \*600374], *BBS5* [2q31.1; OMIM \*603650], *BBS7* [4q27; OMIM \*607590], *BBS8* [14q31.3; OMIM \*608132], *BBS9* [7p14.3; OMIM \*607968], *BBS17* [3p21.31; OMIM \*606568], and *BBS18* [10q25.2; OMIM \*613605]); chaperonin complex (*BBS6* [20p12.2; OMIM \*604896], *BBS10* [12q21.2; OMIM \*610148], and *BBS12* [4q27; OMIM \*610683]); basal body (*BBS13* [17q22; OMIM \*609883], *BBS14* [12q21.32; OMIM \*610142], *BBS15* [2p15; OMIM \*613580], and *BBS16* [1q43‐q44; OMIM \*613524]) or having some related biological function (*BBS3* [3q11.2; OMIM \*608845], *BBS11* [9q33.1; OMIM \*602290], *BBS19* [22q12.3; OMIM \*615870], *BBS20,* and *NPHP1* [2q13; OMIM \*607100]) [74].

Many of these genes appear to affect proteins localized to the basal body, a key element of the monocilium thought to be important for intercellular sensing in mammalian cells including neurons [73]. The literature shows that ciliary function is associated with leptin signaling [93]. As evidenced by some studies in mice, hyperphagia and obesity are caused by conditional post‐natal knockout of proteins involved in intraflagellar transport [94], but they occur also when the loss of cilia affects the neurons, in particular POMC neurons [94].

Alström syndrome (ALMS; OMIM #203800) is a rare genetic disorder that has been included in the ciliopathies group, in the last few years [95].

The estimated prevalence for ALMS is one to nine cases per 1,000,000 individuals with nearly 900 cases described worldwide to date. Symptoms first appear in infancy and progressive development of multi‐organ pathology lead to a reduced life expectancy. Variability in age of

**Figure 3.** BMI growth chart in a girl with Alström syndrome.

onset and severity of clinical symptoms, even within families, are likely due to genetic back‐ ground [95].

[74]. Strikingly, all BBS genes participate in cilia functioning, being a part of BBSome (*BBS1* [11q13.2; OMIM \*209901], *BBS2* [16q13; OMIM \*606151], *BBS4* [15q24.1; OMIM \*600374], *BBS5* [2q31.1; OMIM \*603650], *BBS7* [4q27; OMIM \*607590], *BBS8* [14q31.3; OMIM \*608132], *BBS9* [7p14.3; OMIM \*607968], *BBS17* [3p21.31; OMIM \*606568], and *BBS18* [10q25.2; OMIM \*613605]); chaperonin complex (*BBS6* [20p12.2; OMIM \*604896], *BBS10* [12q21.2; OMIM \*610148], and *BBS12* [4q27; OMIM \*610683]); basal body (*BBS13* [17q22; OMIM \*609883], *BBS14* [12q21.32; OMIM \*610142], *BBS15* [2p15; OMIM \*613580], and *BBS16* [1q43‐q44; OMIM \*613524]) or having some related biological function (*BBS3* [3q11.2; OMIM \*608845], *BBS11* [9q33.1; OMIM \*602290], *BBS19* [22q12.3; OMIM \*615870], *BBS20,* and *NPHP1* [2q13; OMIM

Many of these genes appear to affect proteins localized to the basal body, a key element of the monocilium thought to be important for intercellular sensing in mammalian cells including neurons [73]. The literature shows that ciliary function is associated with leptin signaling [93]. As evidenced by some studies in mice, hyperphagia and obesity are caused by conditional post‐natal knockout of proteins involved in intraflagellar transport [94], but they occur also

Alström syndrome (ALMS; OMIM #203800) is a rare genetic disorder that has been included

The estimated prevalence for ALMS is one to nine cases per 1,000,000 individuals with nearly 900 cases described worldwide to date. Symptoms first appear in infancy and progressive development of multi‐organ pathology lead to a reduced life expectancy. Variability in age of

when the loss of cilia affects the neurons, in particular POMC neurons [94].

in the ciliopathies group, in the last few years [95].

**Figure 3.** BMI growth chart in a girl with Alström syndrome.

\*607100]) [74].

226 Adiposity - Omics and Molecular Understanding

Children typically develop obesity by age 5 years, associated with hyperinsulinemia, chronic hyperglycemia and neurosensory deficits (**Figure 3**) [6]. Children affected by ALMS, like children with BBS, have visual impairment and deafness that occurs early in life but its incidence is higher in these patients as well as NIDDM, found in up to 70% of individuals by age 20 years [96, 97].

In addition, ALMS is also associated with cardiomyopathy, renal anomalies and endocrino‐ pathies such as hypertriglyceridemia, pubertal delay, and hyperandrogenism and growth hormone deficiency [97].

Until now, disease‐causing mutations in the *ALMS1* (2p13.1; OMIM \*606844) gene have been involved in this disorder.

The diagnosis is based on the phenotype of the patient, and it is confirmed when two muta‐ tions in *ALMS1* gene are identifies through molecular analysis.

However, it is difficult to diagnose early ALMS first of all because symptoms arise gradually and secondly because the phenotypes overlap, in particular with BBS in the case of ALMS [98].

In recent times, thanks to the discovery of new genetic tools, in particular next‐generation sequencing (NGS) technology, a large number of patients have been diagnosed. The advent of these new techniques allows early diagnosis also in those patients who do not have a charac‐ teristic phenotype, thus preventing long‐term complications that can be caused by a delay in diagnosis [99].

Today, the most used genetic techniques are whole‐exome sequencing (WES) and whole‐ genome sequencing, thanks to their low cost. However, they are also important because they allow to exclude the mutations in other genes [99, 100].

The WES is a rapid and easier technique because it analyzes all coding regions in the genome [100]. Thanks to it, in fact, mutations in *ALMS1* gene have been identified in individuals, whose phenotype did not seem to be typical of ALMS; therefore, it is fundamental to identifying pathogenic mutations in compound heterozygous state in *ALMS1* gene, overcoming also limitation of genetic panels in patient suffering from familial dilated cardiomyopathy and severe heart failure [101].

In fact, as reported in literature, the association of WES and a previous linkage analysis has allowed to identify the pathogenic mutations in *ALMS1* gene in a consanguineous Turkish family with severe dilated cardiomyopathy although it did not present the typical phenotype of ALMS [102].

Moreover, these mutations have been shown also in consanguineous Leber congenital amaurosis families through homozygosity mapping followed by WES [103].

As evidenced by these studies, the simultaneous use of different genetic techniques is funda‐ mental both in the case of consanguineous families that in patients without the typical ALMS phenotype [95].

For management of the disease and to identify an accurate treatment, it is important for both the present of typical clinical features that an appropriate genetic diagnosis, which may be carried out by NGS techniques, thanks to its low cost compared with traditional polymerase chain reaction and direct Sanger sequencing [103].
