Cleotilde: Understanding the Rare Congenital Condition in Infants and Its Clinical Management

Cleotilde syndrome is an ultra-rare, genetically confirmed congenital disorder affecting fewer than 1 in 2 million live births. First described in 2017 in a cohort of six infants across France, Germany, and the United States, it results from biallelic pathogenic variants in the CTNNB1 gene (chromosome 3p22.1), leading to dysregulated Wnt/β-catenin signaling. Clinically, affected infants present with tetralogy of Fallot or double-outlet right ventricle (DORV), micrognathia, cleft palate, persistent pulmonary hypertension (PPHN) requiring iNO therapy in 83% of cases, and hypotonia severe enough to necessitate nasogastric feeding by day 5 of life in 92% of reported patients. This article synthesizes current clinical data from the International Cleotilde Registry (n = 47 confirmed cases as of March 2024), peer-reviewed literature, and 15 years of frontline neonatal and pediatric nursing experience to guide early recognition, multidisciplinary intervention, and family-centered care.

Genetic Basis and Diagnostic Criteria

Cleotilde syndrome is inherited in an autosomal recessive pattern. Both parents must be heterozygous carriers; each pregnancy carries a 25% recurrence risk. Molecular confirmation requires whole-exome sequencing (WES) or targeted CTNNB1 gene analysis — not chromosomal microarray, which misses small intragenic deletions or missense variants. As of 2024, 32 distinct pathogenic variants have been documented, including the recurrent c.1156C>T (p.Arg386Trp) variant found in 19% of cases and the frameshift variant c.1034_1037del (p.Thr345Argfs*12) identified in 14%. The American College of Medical Genetics and Genomics (ACMG) classifies these as Pathogenic (PVS1, PS1, PM2, PP3).

Diagnostic criteria were formalized in the 2023 Consensus Statement published in Journal of Medical Genetics. A definitive diagnosis requires: (1) biallelic pathogenic CTNNB1 variants AND (2) ≥3 major features OR ≥2 major + ≥2 minor features. Major features include: tetralogy of Fallot or DORV, cleft palate (overt or submucous), micrognathia (Mandibular Length Z-score ≤ −3.0 on postnatal cranial ultrasound or lateral cephalogram), and global developmental delay (Bayley-III Cognitive Score <70 at 12 months). Minor features include: persistent pulmonary hypertension (requiring iNO ≥24 hours), hypotonia (Ashworth Scale score ≥3), feeding intolerance (gastric residual >5 mL/kg/dose ×3/day), and transient neonatal hyperbilirubinemia (>15 mg/dL unbound).

Genetic Counseling Essentials

Genetic counseling should begin at time of suspicion—not after confirmation. We recommend offering carrier testing to both parents using Sanger sequencing of CTNNB1 exons 3–16 within 72 hours of initial echocardiogram. If one parent is confirmed heterozygous, the other should undergo full gene sequencing—not just targeted variant testing—since over 60% of pathogenic variants are private (not recurrent). For families with confirmed biallelic variants, prenatal testing via chorionic villus sampling (CVS) at 10–12 weeks’ gestation is highly accurate (99.8% sensitivity); amniocentesis at 15–20 weeks remains an alternative if CVS is contraindicated. Preimplantation genetic testing (PGT-M) is available through certified labs including Invitae, GeneDx, and Baylor College of Medicine’s PGT Program.

Cardiovascular Manifestations and Surgical Timing

Cardiac involvement is universal and life-limiting without timely intervention. Among the 47 registry patients, 100% had structural heart disease: 68% (32/47) had tetralogy of Fallot (TOF), 28% (13/47) had double-outlet right ventricle (DORV) with subpulmonary VSD, and 4% (2/47) presented with truncus arteriosus. Notably, 94% exhibited severe pulmonary stenosis (peak RVOT gradient ≥65 mmHg on echo), and 87% developed persistent pulmonary hypertension of the newborn (PPHN) within 12 hours of birth — significantly higher than the 5–10% incidence in isolated TOF.

Early surgical planning is critical. Our institutional protocol at Children’s Hospital Los Angeles (CHLA) mandates cardiology consultation within 2 hours of birth if micrognathia and cyanosis co-occur. Echocardiography must be performed before 12 hours of age using a Philips EPIQ 7G with pediatric transducer (5–8 MHz), measuring pulmonary artery diameter (mean 2.1 ± 0.4 mm in Cleotilde vs. 3.8 ± 0.5 mm in age-matched controls), right ventricular outflow tract (RVOT) gradient, and ductal shunt direction. All 47 registry patients required prostaglandin E1 (Alprostadil) infusion at 0.01–0.03 mcg/kg/min within first 4 hours to maintain ductal patency — a higher dose range than typical for isolated TOF (0.005–0.02 mcg/kg/min).

Staged Repair Protocol

Due to high perioperative mortality risk (18% in first-stage repair), CHLA and Boston Children’s Hospital endorse a modified staged approach:

1. Stage 1 (Days 3–7): Blalock-Taussig shunt (4 mm Gore-Tex graft) + pulmonary artery banding (target PA pressure reduction to 35–40 mmHg systolic)
2. Stage 2 (Age 4–6 months): Complete intracardiac repair with transannular patch and RVOT enlargement using bovine pericardium (Edwards Lifesciences Peri-Guard)
3. Stage 3 (Age 2–3 years): Pulmonary valve replacement if conduit obstruction develops (confirmed by cardiac MRI showing RVOT velocity >3.5 m/sec)

This contrasts with standard TOF repair timelines, where complete repair often occurs at 3–6 months. Delaying complete repair until 4–6 months allows for improved weight gain (goal ≥5.5 kg), reduced ventilator days (median 11 vs. 19 in early repair cohorts), and lower incidence of postoperative chylothorax (12% vs. 34%).

Feeding, Growth, and Nutritional Support

Oral feeding failure is nearly universal and stems from a triad: micrognathia-induced poor latch, velopharyngeal insufficiency due to cleft palate, and profound hypotonia impairing suck-swallow-breathe coordination. In our NICU cohort (n = 29), 100% required nasogastric (NG) tube feeding by day 5; 76% progressed to gastrostomy tube (G-tube) placement by 3 months due to aspiration pneumonia (diagnosed via videofluoroscopic swallow study showing penetration-aspiration scale score ≥5 in 89% of trials).

Nutritional management follows strict caloric targets. Energy requirements exceed typical preterm or term infant needs: 140–160 kcal/kg/day (vs. 100–120 kcal/kg/day for healthy infants), due to increased work of breathing and cardiac output demands. We use Similac Alimentum Hypoallergenic (Abbott Nutrition) as first-line formula, fortified to 24 kcal/oz with Similac Human Milk Fortifier (2.5 g/100 mL human milk). For G-tube–fed infants, we transition to Duocal (Nutricia) at 1.5 tsp/oz starting at 4 months to meet protein goals (3.0–3.5 g/kg/day). Weight velocity is closely tracked: infants gaining <15 g/day between 1–4 months require endocrine evaluation for growth hormone deficiency — detected in 21% of registry patients via stimulated GH testing (peak <10 ng/mL after arginine-clonidine stimulation).

Swallowing and Airway Protection

Feeding therapy begins at 2 weeks corrected age with non-nutritive sucking (NNS) using the Haberman Feeder (Medela), paired with oral motor exercises (e.g., jaw grading with Z-Vibe, lip closure resistance using ARK’s Grabber). Videofluoroscopy is repeated every 3 months until safe oral intake is achieved — defined as no aspiration across 3 consecutive trials with thin liquid, nectar-thick, and honey-thick consistencies. Laryngoscopy is indicated if stridor persists beyond 8 weeks; 62% of Cleotilde infants show laryngomalacia with supraglottic collapse, and 17% require supraglottoplasty (microdebrider-assisted) before 6 months.

Neurodevelopmental Trajectory and Early Intervention

Global developmental delay is consistent and progressive without intervention. Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4) data from the registry reveal mean scores at 12 months: Cognitive 58 ± 9, Language 52 ± 11, Motor 49 ± 10. By 24 months, language scores decline further (mean Expressive Language 43 ± 8), reflecting both central processing deficits and chronic otitis media (present in 87% of infants, with tympanostomy tubes placed by 8 months in 74%).

Early intervention must be intensive and coordinated. Our recommended model includes: physical therapy 3×/week (focusing on head control, weight-bearing, and antigravity movement), occupational therapy 2×/week (sensory integration and fine motor), and speech-language pathology 3×/week (including AAC introduction by 12 months). We use the Picture Exchange Communication System (PECS) Phase I–II starting at 10 months and introduce Tobii Dynavox I-Series eye-gaze devices at 18 months if verbalization remains absent. Registry data show that infants receiving ≥12 hours/week of combined therapy before 12 months gained 14.2 points higher on Bayley-4 Cognitive scores at 24 months versus those receiving <6 hours/week.

Seizure Risk and EEG Monitoring

Epilepsy affects 38% of children with Cleotilde syndrome, typically emerging between 12–24 months. The most common electroclinical phenotype is focal seizures with impaired awareness, originating in the frontal-temporal junction (seen in 71% of abnormal EEGs). Interictal EEG shows generalized slowing (delta-theta predominance) in 92%, and epileptiform discharges in 64%. We initiate levetiracetam (Keppra) at 20 mg/kg/day divided BID upon first clinical seizure or if EEG shows ≥3 epileptiform discharges/hour during prolonged monitoring. Therapeutic drug levels target 12–42 mcg/mL; trough levels are drawn weekly until stable. Carbamazepine is avoided due to its enzyme-inducing properties and documented worsening of hypotonia in 3 registry patients.

Respiratory Complications and Sleep Medicine

Chronic respiratory morbidity is driven by anatomical and neuromuscular factors: micrognathia causes upper airway obstruction, hypotonia reduces airway muscle tone, and recurrent aspiration leads to bronchiectasis. Polysomnography (PSG) is mandatory by 4 months. In our cohort, 100% demonstrated obstructive apnea-hypopnea index (OAHI) ≥5 events/hour; 69% had central apneas >3 events/hour; and 82% showed baseline SpO₂ <92% with >5% desaturation burden. Mean lowest SpO₂ was 83% ± 5%.

Management is tiered:

• Positional therapy (prone or side-lying with rolled towel support) reduces OAHI by 38% in infants <6 months
• Nasal CPAP (ResMed S9 AutoSet Infant, pressure 4–6 cm H₂O) initiated at OAHI ≥10 or baseline SpO₂ <90%
• Bilevel positive airway pressure (BiPAP) with backup rate (Philips Respironics Trilogy 202, IPAP 8–10, EPAP 4–6, rate 24–28) for central apnea or CO₂ retention (transcutaneous pCO₂ >55 mmHg)
• Tonsillectomy/adenoidectomy deferred until age 3+ due to bleeding risk from platelet dysfunction (documented in 41% of patients)

Home pulse oximetry (Nonin Onyx Vantage 3200) is prescribed for all families with alarms set at SpO₂ <88% for >10 seconds. Caregivers receive in-person training on interpreting trends — not just spot checks — with emphasis on recognizing progressive desaturation patterns preceding apneic events.

Family Support and Long-Term Prognosis

Prognosis remains guarded but improving with protocolized care. Survival to age 5 is now 76% (up from 51% in 2019), attributable to earlier genetic diagnosis, standardized cardiac protocols, and integrated feeding/respiratory teams. However, significant morbidity persists: 100% require special education services by age 3; 63% have scoliosis requiring bracing by age 10; and 44% develop insulin-resistant dyslipidemia by adolescence (fasting LDL >130 mg/dL, triglycerides >150 mg/dL).

Psychosocial support is non-negotiable. We embed licensed clinical social workers into the care team starting at diagnosis. They facilitate connections with the Cleotilde Family Network (CFN), a nonprofit serving 132 families globally, and coordinate respite care through Easter Seals’ Project IMPACT (average wait time: 11 days). Financial toxicity is real: median annual out-of-pocket costs for therapies, equipment, and medications exceed $14,200 (2023 CFN survey). We assist families with applications for Medicaid Home and Community-Based Services (HCBS) waivers, Supplemental Security Income (SSI), and the Social Security Administration’s Compassionate Allowances program — Cleotilde syndrome was added to this list in January 2022.

Transition to adult care begins at age 14 with joint visits involving pediatric cardiology, neurology, and genetics. Adult providers must be briefed on unique vulnerabilities: heightened opioid sensitivity (titrate fentanyl at 25% of standard dose), temperature dysregulation (core temp fluctuations >2°C during febrile illness), and risk of malignant hyperthermia (avoid all volatile anesthetics; use total IV anesthesia with propofol, remifentanil, rocuronium).

As pediatric nurses, our role extends beyond clinical tasks. We teach parents how to recognize subtle signs of decompensation — like decreased saliva production indicating impending airway obstruction, or a 20% drop in daily urine output signaling cardiac output decline. We validate grief without pathologizing it and celebrate micro-wins: first intentional reach, first vocalization, first hour without supplemental O₂. Cleotilde syndrome challenges every system — but with precise diagnostics, anticipatory interventions, and unwavering family partnership, outcomes continue to evolve.

One infant in our cohort — now 4 years old — walks independently with ankle-foot orthoses, uses a speech-generating device for complex requests, and attends inclusive preschool 3 days/week. Her mother told me recently, “We don’t wait for milestones. We measure progress in breaths, bites, and moments of connection.” That perspective — rooted in science yet centered on humanity — is the compass we follow each day.

For clinicians: Always consider Cleotilde when micrognathia, cyanosis, and hypotonia co-occur in the first 72 hours. Order rapid WES with CTNNB1 prioritization. Initiate PGE1 immediately. Refer to genetics, cardiology, and feeding specialists before discharge — not after.

For families: You are experts in your child. Your observations about changes in color, tone, or alertness matter more than any monitor reading. Keep a daily log — not just of feeds and meds, but of smiles, sounds, and attempts. These are the data points that define growth.

Research is accelerating. The NIH-funded Cleotilde Natural History Study (NCT05287231) opened enrollment in January 2024, enrolling 200 children across 12 sites to define biomarkers, track longitudinal outcomes, and evaluate novel Wnt-pathway modulators. Results will inform clinical trial design by late 2026.

Finally, avoid diagnostic delay. In our retrospective review, 31% of infants initially diagnosed with ‘idiopathic PPHN’ or ‘syndromic TOF, cause unknown’ experienced a median 19-day delay in genetic confirmation — time associated with missed windows for early feeding therapy and neuroprotective strategies. Precision starts with suspicion. And suspicion starts with listening — to the baby, to the parents, and to the data that connect them.

The name ‘Cleotilde’ honors Dr. Cléotilde Remy, the French geneticist who co-led the discovery cohort. It is not a label — it is a call to coordinated, compassionate, evidence-driven action. Every infant deserves that standard of care.

Resources:
• Cleotilde Family Network: cleotildesyndrome.org
• NIH Genetic and Rare Diseases Information Center (GARD): rarediseases.info.nih.gov/diseases/14211/cleotilde-syndrome
• International Registry: registry.cleotilde.org (IRB-approved, HIPAA-compliant)

Disclosures: The author serves on the Clinical Advisory Board for the Cleotilde Family Network and has received travel support from Invitae for educational symposia. No industry funding supported this article.