RIN2 syndrome

What it is

From: Orphanet

RIN2 syndrome, formerly known as macrocephaly, alopecia, cutis laxa and scoliosis (MACS) syndrome, is a very rare inherited connective tissue disorder characterized by macrocephaly, sparse scalp hair, soft-redundant and hyperextensible skin, joint hypermobility, and scoliosis. Patients have progressive facial coarsening with downslanted palpebral fissures, upper eyelid fullness/infraorbital folds, thick/everted vermillion, gingival overgrowth and abnormal position of the teeth. Rarer manifestations such as abnormal high-pitched voice, bronchiectasis, hypergonadotropic hypergonadism and brachydactyly have also been reported.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormal lip morphology · Very frequent (99-80%)

An abnormality of the lip.

Coarse facial features · Very frequent (99-80%)

Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.

Downslanted palpebral fissures · Very frequent (99-80%)

The palpebral fissure inclination is more than two standard deviations below the mean.

Gingival overgrowth · Very frequent (99-80%)

Hyperplasia of the gingiva (that is, a thickening of the soft tissue overlying the alveolar ridge. The degree of thickening ranges from involvement of the interdental papillae alone to gingival overgrowth covering the entire tooth crown.

High palate · Very frequent (99-80%)

Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).

Hirsutism · Very frequent (99-80%)

Abnormally increased hair growth referring to a male pattern of body hair (androgenic hair).

Hyperextensible skin · Very frequent (99-80%)

A condition in which the skin can be stretched beyond normal, and then returns to its initial position.

Infra-orbital fold · Very frequent (99-80%)

Elevated ridge(s) of skin starting well below the medial aspect of the lower lid that curves gradually upward toward and/or across the nasal bridge.

Joint hypermobility · Very frequent (99-80%)

The capability that a joint (or a group of joints) has to move, passively and/or actively, beyond normal limits along physiological axes.

Long philtrum · Very frequent (99-80%)

Distance between nasal base and midline upper lip vermilion border more than 2 SD above the mean. Alternatively, an apparently increased distance between nasal base and midline upper lip vermilion border.

Pes planus · Very frequent (99-80%)

A foot where the longitudinal arch of the foot is in contact with the ground or floor when the individual is standing; or, in a patient lying supine, a foot where the arch is in contact with the surface of a flat board pressed against the sole of the foot by the examiner with a pressure similar to that expected from weight bearing; or, the height of the arch is reduced.

Redundant skin · Very frequent (99-80%)

Loose and sagging skin often associated with loss of skin elasticity.

Scoliosis · Very frequent (99-80%)

The presence of an abnormal lateral curvature of the spine.

Sparse scalp hair · Very frequent (99-80%)

Decreased number of hairs per unit area of skin of the scalp.

Other findings in the same source

From: Orphanet

Additional reported features include Upper eyelid edema (Very frequent (99-80%)); Irregular dentition (Very frequent (99-80%)); Abnormal sternum morphology (Frequent (79-30%)); Abnormally high-pitched voice (Frequent (79-30%)); Bruising susceptibility (Frequent (79-30%)); Cognitive impairment (Frequent (79-30%)); Umbilical hernia (Frequent (79-30%)); Aortic aneurysm (Occasional (29-5%)); Brachydactyly (Occasional (29-5%)); Cryptorchidism (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

When it may begin

From: Orphanet

Infancy; Neonatal

Inheritance in the source

From: Orphanet

Autosomal recessive

Frequency and the population described

From: Orphanet

Reported case(s): 10.0; Worldwide. This is a published case count, not prevalence. Point prevalence: <1 / 1 000 000; Worldwide; Class only.

Understanding the inheritance label

From: MedlinePlus Genetics

An autosomal recessive pattern usually involves disease-causing changes in both copies of a gene. Parents may each carry one altered copy without having the condition themselves. A genetic counsellor can explain carrier testing and reproductive implications using the actual laboratory findings, rather than the condition name alone.

Which doctor should you see?

The suggested department for discussing RIN2 syndrome is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for RIN2 syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.